DOI: 10.1148/rg.262055059
RadioGraphics 2006;26:389-405
© RSNA, 2006
Prenatal US and MR Imaging Findings of Lissencephaly: Review of Fetal Cerebral Sulcal Development1
Sandeep Ghai, MD,
Katherine W. Fong, MB, BS, FRCPC,
Ants Toi, MD, FRCPC,
David Chitayat, MD, FRCPC,
Sophia Pantazi, MD, FRCPC and
Susan Blaser, MD, FRCPC
1 From the Department of Medical Imaging (S.G., K.W.F., A.T., S.P., S.B.) and Prenatal Diagnosis and Medical Genetics Program (D.C.), Mount Sinai Hospital and University of Toronto, 600 University Ave, Room 570, Toronto, Ontario, Canada M5G 1X5; and Division of Clinical and Metabolic Genetics (D.C.) and Department of Diagnostic Imaging (S.B.), Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. Recipient of a Certificate of Merit award for an education exhibit at the 2003 RSNA Annual Meeting. Received March 22, 2005; revision requested May 11; revision received and accepted June 13. All authors have no financial relationships to disclose. K.W.F. supported by an RSNA Research Seed Grant.
Address correspondence to K.W.F. (e-mail: katherine.fong{at}sympatico.ca).
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Abstract
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The cerebral cortex develops in three overlapping stages: cell proliferation, neuronal migration, and cortical organization. Abnormal neuronal migration may result in lissencephaly, which is characterized by either the absence (agyria) or the paucity (pachygyria) of cerebral convolutions. The two main clinicopathologic types of lissencephaly may be differentiated according to their prenatal imaging features. Other cranial and extracranial abnormalities also may occur in association with lissencephaly. The prognosis is often poor, but prenatal diagnosis allows appropriate counseling and optimization of obstetric management. Familiarity with the normal ultrasonographic (US) and magnetic resonance (MR) imaging appearances of the fetal cerebral cortex at various stages of gestation is essential for the early detection of abnormal sulcal development. The primary fissures and sulci that can be examined with prenatal US and MR imaging include the parieto-occipital fissure, calcarine fissure, cingulate sulcus, convexity sulci, and sylvian fissure and insula.
© RSNA, 2006
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LEARNING OBJECTIVES
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After reading this article and taking the test, the reader will be able to:- Describe the features of normal cerebral sulcal development on prenatal US and MR images.
- Recognize prenatal US and MR imaging features of lissencephaly.
- Discuss potential pitfalls and limitations of US and MR imaging for the diagnosis of lissencephaly.
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Introduction
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The three main overlapping steps in the development of the cerebral cortex are cell proliferation, neuronal migration, and cortical organization. Neuronal migration starts during the 8th week of gestation and is responsible for the formation of the normal six-layered cortex. Lissencephaly (smooth brain) is a severe malformation of the cerebral cortex that results from impaired neuronal migration during the 3rd and 4th months of gestation (1). The affected brain shows either an absence or a paucity of gyri (agyria or pachygyria, respectively).
The most common clinical manifestations include severe psychomotor retardation, developmental delay, seizures, and failure to thrive. The prognosis depends on the degree of failure of cortical development. In severe cases, death occurs in infancy or early childhood. Prenatal diagnosis of an affected fetus allows appropriate counseling and optimization of obstetric management.
Abnormal cortical development is the main manifestation of lissencephaly, although other associated cranial and extracranial abnormalities may be present. Familiarity with the normal ultrasonographic (US) and magnetic resonance (MR) imaging appearance of the fetal cerebral cortex at various stages of gestation is essential for the early diagnosis of this disorder.
In this article, we review the features of normal cerebral sulcal development on prenatal US and MR images, describe prenatal US findings of lissencephaly with MR imaging correlation, and discuss potential pitfalls and limitations of US and MR imaging for the diagnosis of lissencephaly.
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Normal Appearance of Cerebral Fissures and Sulci
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There is a correlation between the results of research studies of fetal cerebral sulcal development with the use of anatomic (ie, postmortem), US, and MR imaging examinations (2–9). However, the agreement is not perfect, likely because of limitations of the different techniques, different methods for determining fetal age (weeks since the last menstrual period [2,3], US dating [5,6], or a combination of both [7–9]), and different definitions used in assignment of sulcal appearance times (the fetal age reported for a certain sulcus was based on its depiction in 25%–50% of brains [2], in more than 75% of fetuses [5,6], or in 100% of fetuses [8,9]). In general, sulcal visibility in normal fetuses at imaging lags behind that reported for anatomic examinations. Nevertheless, the progressive appearance of cerebral fissures and sulci on prenatal US and MR images may allow estimation of the extent of brain maturation in a fetus. The absence or abnormal appearance of a particular sulcus at the appropriate fetal age should raise suspicion about the possibility of abnormal or delayed cortical development.
Primary sulci are indentations that appear on the brain surface. Secondary and tertiary sulci are ramifications of the primary sulci and appear at a later stage of development. At US, early sulcal development is best depicted on images obtained perpendicular to the expected course of the sulci (8). A fissure or sulcus is first seen as a small dot or dimple on the surface of the brain. Later, an obvious V-shaped indentation forms. Finally, the indentation deepens and is visible as a surface notch and an echogenic line that extends into the brain in a Y-shaped configuration. US is useful for the evaluation of primary sulci on the medial hemispheric surface (parieto-occipital fissure, calcarine fissure, and cingulate sulcus) and on the lateral convex hemispheric surface (central, post-central, and superior temporal sulci) (7,8).
MR imaging can provide a more complete and global depiction of cerebral sulci and gyri than can US, since visibility at MR imaging is not restricted by cranial bones or fetal position. For fetal MR imaging at most institutions, written maternal consent is obtained. The mother is not sedated, and a torso coil with manually triggered respiratory gating is used for all image acquisitions. T2-weighted single-shot fast spin-echo (SSFSE) images are obtained to define brain anatomy in the axial, coronal, and sagittal planes. Additional T1-weighted, diffusion-weighted, and T2*-weighted sequences may be obtained as needed for detection of blood products or ischemia.
Gestational ages (in weeks after the last normal menstrual period) at the appearance of primary fissures and sulci at anatomic examination and on US and MR images are shown in Table 1. In general, the sulci on the medial hemispheric surface appear earlier than do the lateral convexity sulci.
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Table 1. Gestational Age When Primary Fissures and Sulci Become Visible at Anatomic, US, and MR Imaging Examinations
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Parieto-occipital Fissure
This fissure, which separates the parietal lobe from the occipital lobe, is seen as a deep cleft that extends downward and forward on the medial surface of the brain (Fig 1a). Its major part is on the medial surface of the hemisphere, although a small part is situated on the lateral surface. On US images, the fissure is best depicted in an axial plane near the upper margin of the occipital horns of the lateral ventricles (Fig 1b, 1c). On MR images, it is well depicted in axial and sagittal planes (Fig 1d, 1e).
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Figure 1a. Development of the parieto-occipital fissure. (a) Photograph of the medial hemispheric surface of the fetal brain at 22 weeks of gestation. The red line represents the axial imaging plane through the parieto-occipital fissure, which is highlighted in green. (b) Axial US image of a 21-week fetus shows an echogenic focus (arrow) on the medial surface of the brain, at the level of the lateral ventricle. (c) Axial US image of a 26-week fetus shows further indentation (arrow). (d, e) Axial (d) and sagittal (e) T2-weighted SSFSE MR images of a 27-week fetus show the parieto-occipital fissure on the medial surface of the brain (white arrow), the calcarine fissure (arrowhead), and the central sulcus (black arrow). (Fig 1a modified and reprinted, with permission, from reference 3.)
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Figure 1b. Development of the parieto-occipital fissure. (a) Photograph of the medial hemispheric surface of the fetal brain at 22 weeks of gestation. The red line represents the axial imaging plane through the parieto-occipital fissure, which is highlighted in green. (b) Axial US image of a 21-week fetus shows an echogenic focus (arrow) on the medial surface of the brain, at the level of the lateral ventricle. (c) Axial US image of a 26-week fetus shows further indentation (arrow). (d, e) Axial (d) and sagittal (e) T2-weighted SSFSE MR images of a 27-week fetus show the parieto-occipital fissure on the medial surface of the brain (white arrow), the calcarine fissure (arrowhead), and the central sulcus (black arrow). (Fig 1a modified and reprinted, with permission, from reference 3.)
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Figure 1c. Development of the parieto-occipital fissure. (a) Photograph of the medial hemispheric surface of the fetal brain at 22 weeks of gestation. The red line represents the axial imaging plane through the parieto-occipital fissure, which is highlighted in green. (b) Axial US image of a 21-week fetus shows an echogenic focus (arrow) on the medial surface of the brain, at the level of the lateral ventricle. (c) Axial US image of a 26-week fetus shows further indentation (arrow). (d, e) Axial (d) and sagittal (e) T2-weighted SSFSE MR images of a 27-week fetus show the parieto-occipital fissure on the medial surface of the brain (white arrow), the calcarine fissure (arrowhead), and the central sulcus (black arrow). (Fig 1a modified and reprinted, with permission, from reference 3.)
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Figure 1d. Development of the parieto-occipital fissure. (a) Photograph of the medial hemispheric surface of the fetal brain at 22 weeks of gestation. The red line represents the axial imaging plane through the parieto-occipital fissure, which is highlighted in green. (b) Axial US image of a 21-week fetus shows an echogenic focus (arrow) on the medial surface of the brain, at the level of the lateral ventricle. (c) Axial US image of a 26-week fetus shows further indentation (arrow). (d, e) Axial (d) and sagittal (e) T2-weighted SSFSE MR images of a 27-week fetus show the parieto-occipital fissure on the medial surface of the brain (white arrow), the calcarine fissure (arrowhead), and the central sulcus (black arrow). (Fig 1a modified and reprinted, with permission, from reference 3.)
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Figure 1e. Development of the parieto-occipital fissure. (a) Photograph of the medial hemispheric surface of the fetal brain at 22 weeks of gestation. The red line represents the axial imaging plane through the parieto-occipital fissure, which is highlighted in green. (b) Axial US image of a 21-week fetus shows an echogenic focus (arrow) on the medial surface of the brain, at the level of the lateral ventricle. (c) Axial US image of a 26-week fetus shows further indentation (arrow). (d, e) Axial (d) and sagittal (e) T2-weighted SSFSE MR images of a 27-week fetus show the parieto-occipital fissure on the medial surface of the brain (white arrow), the calcarine fissure (arrowhead), and the central sulcus (black arrow). (Fig 1a modified and reprinted, with permission, from reference 3.)
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Calcarine Fissure
This fissure is seen on the medial surface of the occipital lobe (Fig 2a). It starts from the medial part of the parieto-occipital fissure and extends posteriorly to the occipital pole. On both US and MR images, it is best depicted in a coronal plane through the occipital lobes, where it is seen immediately superior to the tentorium (Fig 2b, 2c). It also can be identified on sagittal MR images (Fig 1e).
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Figure 2a. Calcarine fissure. (a) Photograph of the medial hemispheric surface of the fetal brain at 22 weeks of gestation. The red line represents the coronal imaging plane through the calcarine fissure, which is highlighted in green. (b, c) Coronal US image of a 23-week fetus (b) and coronal T2-weighted SSFSE MR image of a 27-week fetus (c) depict the calcarine fissure on the medial cerebral surface (arrow). V = lateral ventricle. (Fig 2a modified and reprinted, with permission, from reference 3.)
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Figure 2b. Calcarine fissure. (a) Photograph of the medial hemispheric surface of the fetal brain at 22 weeks of gestation. The red line represents the coronal imaging plane through the calcarine fissure, which is highlighted in green. (b, c) Coronal US image of a 23-week fetus (b) and coronal T2-weighted SSFSE MR image of a 27-week fetus (c) depict the calcarine fissure on the medial cerebral surface (arrow). V = lateral ventricle. (Fig 2a modified and reprinted, with permission, from reference 3.)
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Figure 2c. Calcarine fissure. (a) Photograph of the medial hemispheric surface of the fetal brain at 22 weeks of gestation. The red line represents the coronal imaging plane through the calcarine fissure, which is highlighted in green. (b, c) Coronal US image of a 23-week fetus (b) and coronal T2-weighted SSFSE MR image of a 27-week fetus (c) depict the calcarine fissure on the medial cerebral surface (arrow). V = lateral ventricle. (Fig 2a modified and reprinted, with permission, from reference 3.)
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Cingulate Sulcus
The cingulate sulcus is seen on the medial surface of the brain (Fig 3a). It begins below the anterior end of the corpus callosum and runs upward and forward, nearly paralleling the rostrum, and then ascends in parallel with the body of the corpus callosum to the superomedial border of the hemisphere, a short distance behind the upper end of the central sulcus. Because of the curved course of the sulcus, the anterior part is well depicted on axial images, and the middle part is best visualized on coronal images (Fig 3b, 3c).
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Figure 3a. Cingulate sulcus. (a) Photograph of the medial hemispheric surface of the fetal brain at 28 weeks of gestation. The red line represents the coronal imaging plane through the cingulate sulcus, which is highlighted in green. (b) Coronal T2-weighted SSFSE MR image of a 28-week fetus shows a well-defined cingulate sulcus (arrow) and the sylvian fissure (arrowhead) with margins that form acute angles with the base. (c) Coronal US image of a 29-week fetus shows the cingulate sulcus as an echogenic line (arrow) and the sylvian fissure (arrowhead). (Fig 3a modified and reprinted, with permission, from reference 3.)
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Figure 3b. Cingulate sulcus. (a) Photograph of the medial hemispheric surface of the fetal brain at 28 weeks of gestation. The red line represents the coronal imaging plane through the cingulate sulcus, which is highlighted in green. (b) Coronal T2-weighted SSFSE MR image of a 28-week fetus shows a well-defined cingulate sulcus (arrow) and the sylvian fissure (arrowhead) with margins that form acute angles with the base. (c) Coronal US image of a 29-week fetus shows the cingulate sulcus as an echogenic line (arrow) and the sylvian fissure (arrowhead). (Fig 3a modified and reprinted, with permission, from reference 3.)
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Figure 3c. Cingulate sulcus. (a) Photograph of the medial hemispheric surface of the fetal brain at 28 weeks of gestation. The red line represents the coronal imaging plane through the cingulate sulcus, which is highlighted in green. (b) Coronal T2-weighted SSFSE MR image of a 28-week fetus shows a well-defined cingulate sulcus (arrow) and the sylvian fissure (arrowhead) with margins that form acute angles with the base. (c) Coronal US image of a 29-week fetus shows the cingulate sulcus as an echogenic line (arrow) and the sylvian fissure (arrowhead). (Fig 3a modified and reprinted, with permission, from reference 3.)
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Convexity Sulci
As the fetus matures, these sulci can be seen on the lateral surfaces of the cerebral hemispheres (Fig 4a). The convexity sulci include the central (rolandic) sulcus, superior temporal sulcus, and any other sulcus on the lateral hemispheric surface. In a normal fetus, the central sulcus is identifiable on MR images obtained at 26–27 weeks of gestation (Fig 4b) (9). Since the central sulcus develops initially in the high parietal regions, its visualization with US is hindered by cranial bones. At US, convexity sulci are best imaged semiaxially, through the window of the squamosal suture in the near field and with angulation of the plane of imaging on the farther brain surface from the level of the insula superiorly (Fig 4c, 4d). MR imaging with the use of axial, coronal, and sagittal planes is superior to US in demonstrating sulci of the lateral and inferior surfaces of the cerebral hemispheres (Fig 4e).
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Figure 4a. Convexity sulci. (a) Photograph of the lateral hemispheric surface of the fetal brain at 28 weeks of gestation. Red lines represent the axial US imaging planes (A, B) through the cerebral sulci, which are highlighted in green. (b) Sagittal T2-weighted SSFSE MR image of a 27-week fetus shows the rolandic (central) sulcus (arrow). (c, d) Axial US images of a 28-week fetus (plane A) (c) and a 33-week fetus (plane B) (d) show developing sulci on the lateral hemispheric surface (arrows). (e) Axial T2-weighted SSFSE MR image of a 34-week fetus shows the development of sulci on the lateral hemispheric surface (arrows). (Fig 4a modified and reprinted, with permission, from reference 4.)
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Figure 4b. Convexity sulci. (a) Photograph of the lateral hemispheric surface of the fetal brain at 28 weeks of gestation. Red lines represent the axial US imaging planes (A, B) through the cerebral sulci, which are highlighted in green. (b) Sagittal T2-weighted SSFSE MR image of a 27-week fetus shows the rolandic (central) sulcus (arrow). (c, d) Axial US images of a 28-week fetus (plane A) (c) and a 33-week fetus (plane B) (d) show developing sulci on the lateral hemispheric surface (arrows). (e) Axial T2-weighted SSFSE MR image of a 34-week fetus shows the development of sulci on the lateral hemispheric surface (arrows). (Fig 4a modified and reprinted, with permission, from reference 4.)
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Figure 4c. Convexity sulci. (a) Photograph of the lateral hemispheric surface of the fetal brain at 28 weeks of gestation. Red lines represent the axial US imaging planes (A, B) through the cerebral sulci, which are highlighted in green. (b) Sagittal T2-weighted SSFSE MR image of a 27-week fetus shows the rolandic (central) sulcus (arrow). (c, d) Axial US images of a 28-week fetus (plane A) (c) and a 33-week fetus (plane B) (d) show developing sulci on the lateral hemispheric surface (arrows). (e) Axial T2-weighted SSFSE MR image of a 34-week fetus shows the development of sulci on the lateral hemispheric surface (arrows). (Fig 4a modified and reprinted, with permission, from reference 4.)
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Figure 4d. Convexity sulci. (a) Photograph of the lateral hemispheric surface of the fetal brain at 28 weeks of gestation. Red lines represent the axial US imaging planes (A, B) through the cerebral sulci, which are highlighted in green. (b) Sagittal T2-weighted SSFSE MR image of a 27-week fetus shows the rolandic (central) sulcus (arrow). (c, d) Axial US images of a 28-week fetus (plane A) (c) and a 33-week fetus (plane B) (d) show developing sulci on the lateral hemispheric surface (arrows). (e) Axial T2-weighted SSFSE MR image of a 34-week fetus shows the development of sulci on the lateral hemispheric surface (arrows). (Fig 4a modified and reprinted, with permission, from reference 4.)
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Figure 4e. Convexity sulci. (a) Photograph of the lateral hemispheric surface of the fetal brain at 28 weeks of gestation. Red lines represent the axial US imaging planes (A, B) through the cerebral sulci, which are highlighted in green. (b) Sagittal T2-weighted SSFSE MR image of a 27-week fetus shows the rolandic (central) sulcus (arrow). (c, d) Axial US images of a 28-week fetus (plane A) (c) and a 33-week fetus (plane B) (d) show developing sulci on the lateral hemispheric surface (arrows). (e) Axial T2-weighted SSFSE MR image of a 34-week fetus shows the development of sulci on the lateral hemispheric surface (arrows). (Fig 4a modified and reprinted, with permission, from reference 4.)
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Sylvian Fissure and Insula
The sylvian fissure and insula (Fig 5a) demonstrate a characteristic pattern of development. In early pregnancy, the sylvian fossa appears as a smooth-margined indentation on the lateral surface of the cerebral hemisphere (Fig 5b). After about 17 weeks of gestation, the appearance of the smooth sylvian fossa indentation (insula) begins to change at the site of the developing circular sulcus (8). The insula takes on a plateaulike appearance, with angulation at the margins (the circular sulcus), where it meets the frontal, parietal, and temporal opercula. Because the insula does not expand at the same rate as the part of the cortex that surrounds it, the opercula gradually overgrow the insula as the composite sylvian fissure forms. On prenatal US and MR images, the insular-opercular angles are initially obtuse (>90°) (Fig 5c, 5d), but the angulation becomes acute (>90°) as gestation progresses (Fig 5e, 5f). The sylvian fissure and insula are best assessed on axial US images, where an acute angle between the insula and the temporal lobe operculum should be visible in all normal fetuses after 24.5 weeks of gestation (8). The developing sylvian fissure also can be assessed on axial and coronal MR images (Figs 3b, 5c, 5f).
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Figure 5a. Normal development of the sylvian fissure. (a) Photograph of the lateral hemispheric surface of the fetal brain at 24 weeks of gestation. The red line represents the axial imaging plane through the sylvian fissure, which is highlighted in green. (b) Axial US image of a 17-week fetus shows a smooth, shallow depression on the lateral surface of the brain (arrowhead), a feature that is also depicted diagrammatically with a red line. This is the first recognizable appearance of the sylvian fissure. (c) Axial T2-weighted SSFSE MR image of a 20-week fetus shows a smooth sylvian indentation (arrow). (d) Axial US image of a 21-week fetus shows further indentation (arrowhead), with distinct angularity at the margins of the insula. The margins form an obtuse angle with the base, as depicted diagrammatically with a red line. (e, f) Axial US image of a 26-week fetus (e) and axial T2-weighted SSFSE MR image of a 27-week fetus (f) show an infolding of margins that form acute angles with the base (arrowhead in e, arrow in f), as depicted diagrammatically with the red line in e. These features should be visible in all normal fetuses after 24.5 weeks. (Fig 5a modified and reprinted, with permission, from reference 4.)
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Figure 5b. Normal development of the sylvian fissure. (a) Photograph of the lateral hemispheric surface of the fetal brain at 24 weeks of gestation. The red line represents the axial imaging plane through the sylvian fissure, which is highlighted in green. (b) Axial US image of a 17-week fetus shows a smooth, shallow depression on the lateral surface of the brain (arrowhead), a feature that is also depicted diagrammatically with a red line. This is the first recognizable appearance of the sylvian fissure. (c) Axial T2-weighted SSFSE MR image of a 20-week fetus shows a smooth sylvian indentation (arrow). (d) Axial US image of a 21-week fetus shows further indentation (arrowhead), with distinct angularity at the margins of the insula. The margins form an obtuse angle with the base, as depicted diagrammatically with a red line. (e, f) Axial US image of a 26-week fetus (e) and axial T2-weighted SSFSE MR image of a 27-week fetus (f) show an infolding of margins that form acute angles with the base (arrowhead in e, arrow in f), as depicted diagrammatically with the red line in e. These features should be visible in all normal fetuses after 24.5 weeks. (Fig 5a modified and reprinted, with permission, from reference 4.)
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Figure 5c. Normal development of the sylvian fissure. (a) Photograph of the lateral hemispheric surface of the fetal brain at 24 weeks of gestation. The red line represents the axial imaging plane through the sylvian fissure, which is highlighted in green. (b) Axial US image of a 17-week fetus shows a smooth, shallow depression on the lateral surface of the brain (arrowhead), a feature that is also depicted diagrammatically with a red line. This is the first recognizable appearance of the sylvian fissure. (c) Axial T2-weighted SSFSE MR image of a 20-week fetus shows a smooth sylvian indentation (arrow). (d) Axial US image of a 21-week fetus shows further indentation (arrowhead), with distinct angularity at the margins of the insula. The margins form an obtuse angle with the base, as depicted diagrammatically with a red line. (e, f) Axial US image of a 26-week fetus (e) and axial T2-weighted SSFSE MR image of a 27-week fetus (f) show an infolding of margins that form acute angles with the base (arrowhead in e, arrow in f), as depicted diagrammatically with the red line in e. These features should be visible in all normal fetuses after 24.5 weeks. (Fig 5a modified and reprinted, with permission, from reference 4.)
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Figure 5d. Normal development of the sylvian fissure. (a) Photograph of the lateral hemispheric surface of the fetal brain at 24 weeks of gestation. The red line represents the axial imaging plane through the sylvian fissure, which is highlighted in green. (b) Axial US image of a 17-week fetus shows a smooth, shallow depression on the lateral surface of the brain (arrowhead), a feature that is also depicted diagrammatically with a red line. This is the first recognizable appearance of the sylvian fissure. (c) Axial T2-weighted SSFSE MR image of a 20-week fetus shows a smooth sylvian indentation (arrow). (d) Axial US image of a 21-week fetus shows further indentation (arrowhead), with distinct angularity at the margins of the insula. The margins form an obtuse angle with the base, as depicted diagrammatically with a red line. (e, f) Axial US image of a 26-week fetus (e) and axial T2-weighted SSFSE MR image of a 27-week fetus (f) show an infolding of margins that form acute angles with the base (arrowhead in e, arrow in f), as depicted diagrammatically with the red line in e. These features should be visible in all normal fetuses after 24.5 weeks. (Fig 5a modified and reprinted, with permission, from reference 4.)
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Figure 5e. Normal development of the sylvian fissure. (a) Photograph of the lateral hemispheric surface of the fetal brain at 24 weeks of gestation. The red line represents the axial imaging plane through the sylvian fissure, which is highlighted in green. (b) Axial US image of a 17-week fetus shows a smooth, shallow depression on the lateral surface of the brain (arrowhead), a feature that is also depicted diagrammatically with a red line. This is the first recognizable appearance of the sylvian fissure. (c) Axial T2-weighted SSFSE MR image of a 20-week fetus shows a smooth sylvian indentation (arrow). (d) Axial US image of a 21-week fetus shows further indentation (arrowhead), with distinct angularity at the margins of the insula. The margins form an obtuse angle with the base, as depicted diagrammatically with a red line. (e, f) Axial US image of a 26-week fetus (e) and axial T2-weighted SSFSE MR image of a 27-week fetus (f) show an infolding of margins that form acute angles with the base (arrowhead in e, arrow in f), as depicted diagrammatically with the red line in e. These features should be visible in all normal fetuses after 24.5 weeks. (Fig 5a modified and reprinted, with permission, from reference 4.)
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Figure 5f. Normal development of the sylvian fissure. (a) Photograph of the lateral hemispheric surface of the fetal brain at 24 weeks of gestation. The red line represents the axial imaging plane through the sylvian fissure, which is highlighted in green. (b) Axial US image of a 17-week fetus shows a smooth, shallow depression on the lateral surface of the brain (arrowhead), a feature that is also depicted diagrammatically with a red line. This is the first recognizable appearance of the sylvian fissure. (c) Axial T2-weighted SSFSE MR image of a 20-week fetus shows a smooth sylvian indentation (arrow). (d) Axial US image of a 21-week fetus shows further indentation (arrowhead), with distinct angularity at the margins of the insula. The margins form an obtuse angle with the base, as depicted diagrammatically with a red line. (e, f) Axial US image of a 26-week fetus (e) and axial T2-weighted SSFSE MR image of a 27-week fetus (f) show an infolding of margins that form acute angles with the base (arrowhead in e, arrow in f), as depicted diagrammatically with the red line in e. These features should be visible in all normal fetuses after 24.5 weeks. (Fig 5a modified and reprinted, with permission, from reference 4.)
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Lissencephaly
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Classification
Traditionally, cases of lissencephaly have been divided into two groups based on clinicopathologic type. In type I or classic lissencephaly, the normal six-layer cortex seen at histologic analysis is replaced by an abnormally thick, remodeled, four-layer cortex. Classic lissencephaly may result from an isolated lissencephaly sequence or may be associated with Miller-Dieker syndrome or Norman-Roberts syndrome. Dobyns et al (10) described a grading system for type I lissencephaly, with degrees of severity ranging from diffuse agyria to mixed agyria and pachygyria, pachygyria only, and subcortical band heterotopia. Clinically, Miller-Dieker syndrome can be differentiated from isolated lissencephaly sequence by the presence of facial dysmorphism and a more severe grade of lissencephaly. Miller-Dieker syndrome is the form of lissencephaly most easily recognized on prenatal images because of the striking and total lack of sulci. Other forms may escape prenatal detection because milder or lesser degrees of sulcal developmental arrest may occur after the primary sulci have formed.
Type II lissencephaly is pathologically distinct from type I and, at histologic analysis, is characterized by a disorganized unlayered cortex. While in type I lissencephaly many neurons fail to reach the cortical plate, in type II lissencephaly many neurons move too far into the subpial space (11–13). Type II lissencephaly, also known as cobblestone complex, is observed in some forms of congenital muscular dystrophy that are associated with cortical maldevelopment, including Walker-Warburg (also known as HARD±E [hydrocephalus, agyria, and retinal dysplasia with or without encephalocele]) syndrome, muscle-eye-brain disease, and Fukuyama-type congenital muscular dystrophy. The diagnostic criteria for Walker-Warburg syndrome as described by Dobyns et al (14) include type II lissencephaly, cerebellar malformation, retinal malformation, and congenital muscular dystrophy. Brainstem abnormalities also may be present. They are difficult to detect at fetal US, but MR images demonstrate specific findings.
In a more recent classification system proposed by Barkovich et al (15), malformations due to abnormal neuronal migration are categorized in three main groups. Group A, also known as the lissencephaly–subcortical band heterotopia spectrum, includes type I or classic lissencephaly, as well as lissencephaly with agenesis of the corpus callosum, lissencephaly with cerebellar hypoplasia, and lissencephaly not yet classified. Group B, also known as cobblestone complex, includes type II lissencephaly. Group C comprises heterotopias other than subcortical band heterotopia.
Prenatal Diagnosis with US
Most cases of Miller-Dieker syndrome and isolated lissencephaly sequence are sporadic and difficult to diagnose. In Miller-Dieker syndrome, intracranial abnormalities include agyria with or without pachygyria, mild ventriculomegaly, and prominent subarachnoid space. The first reported diagnosis at US of lissencephaly associated with Miller-Dieker syndrome was based on the specific finding of a smooth brain surface in two fetuses at 31 and 31.5 weeks of gestation (16). Subsequently, there was another case report of prenatal diagnosis with US at 27 weeks (17). Recently, it was reported that lissencephaly associated with Miller-Dieker syndrome may be suggested by specific findings on prenatal US images obtained at 23 weeks of gestation. Those findings include absence of the parieto-occipital fissure (Fig 6), absence of the calcarine fissure (Fig 7), and an abnormal appearance of the sylvian fissure and insula (18). A smooth, shallow sylvian fissure at 23 weeks of gestation is an abnormal finding that is due to opercular malformation (Figs 8a, 9a). Other findings of delayed cortical development, such as the absence of the cingulate sulcus (Fig 10) or of the convexity sulci (Fig 9a), become evident later, generally after 24 weeks of gestation. In a recent retrospective study of seven fetuses with Miller-Dieker syndrome, mild ventriculomegaly was present in six fetuses at the time of the first US examination, which was performed between 20 and 33 weeks of gestation (18). Other cranial and extracranial US findings are listed in Table 2.
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Figure 6. Abnormal development of the parieto-occipital and calcarine fissures in a 23-week fetus with Miller-Dieker syndrome. Axial US image shows the absence of the parieto-occipital fissure from the expected location (arrow) on the medial hemispheric surface.
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Figure 7. Abnormal development of the parieto-occipital and calcarine fissures in a 23-week fetus with Miller-Dieker syndrome. Coronal US image shows the absence of the calcarine fissure from the expected location (arrow) on the medial hemispheric surface. (Figs 6 and 7 reprinted, with permission, from reference 18.)
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Figure 8a. Lissencephaly associated with Miller-Dieker syndrome. (a) Axial US image of a 26-week fetus shows a flat appearance of the sylvian fissure (large arrow), which is abnormal in a fetus of this gestational age, as well as mild ventriculomegaly (V) and absence of the parieto-occipital fissure (small arrow). (b, c) Axial (b) and coronal (c) T2-weighted SSFSE MR images at 28 weeks of gestation help confirm the abnormal opercular formation of the insula (arrow).
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Figure 8b. Lissencephaly associated with Miller-Dieker syndrome. (a) Axial US image of a 26-week fetus shows a flat appearance of the sylvian fissure (large arrow), which is abnormal in a fetus of this gestational age, as well as mild ventriculomegaly (V) and absence of the parieto-occipital fissure (small arrow). (b, c) Axial (b) and coronal (c) T2-weighted SSFSE MR images at 28 weeks of gestation help confirm the abnormal opercular formation of the insula (arrow).
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Figure 8c. Lissencephaly associated with Miller-Dieker syndrome. (a) Axial US image of a 26-week fetus shows a flat appearance of the sylvian fissure (large arrow), which is abnormal in a fetus of this gestational age, as well as mild ventriculomegaly (V) and absence of the parieto-occipital fissure (small arrow). (b, c) Axial (b) and coronal (c) T2-weighted SSFSE MR images at 28 weeks of gestation help confirm the abnormal opercular formation of the insula (arrow).
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Figure 9a. Lissencephaly associated with Miller-Dieker syndrome. Axial US image of a 32-week fetus shows an abnormal flat insula (arrow), a smooth brain surface, and mild ventriculomegaly (14 mm) as indicated by calipers. (b) Axial T2-weighted SSFSE MR image shows the flat insula (arrow), the smooth cortex, and colpocephaly. A normal cavum septum pellucidum (*) also is visible. (c) Coronal cut section of the brain at 34 weeks shows the smooth cortex and flat insula (arrow).
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Figure 9b. Lissencephaly associated with Miller-Dieker syndrome. Axial US image of a 32-week fetus shows an abnormal flat insula (arrow), a smooth brain surface, and mild ventriculomegaly (14 mm) as indicated by calipers. (b) Axial T2-weighted SSFSE MR image shows the flat insula (arrow), the smooth cortex, and colpocephaly. A normal cavum septum pellucidum (*) also is visible. (c) Coronal cut section of the brain at 34 weeks shows the smooth cortex and flat insula (arrow).
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Figure 9c. Lissencephaly associated with Miller-Dieker syndrome. Axial US image of a 32-week fetus shows an abnormal flat insula (arrow), a smooth brain surface, and mild ventriculomegaly (14 mm) as indicated by calipers. (b) Axial T2-weighted SSFSE MR image shows the flat insula (arrow), the smooth cortex, and colpocephaly. A normal cavum septum pellucidum (*) also is visible. (c) Coronal cut section of the brain at 34 weeks shows the smooth cortex and flat insula (arrow).
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Figure 10. Absence of the cingulate sulcus. Coronal US image of a 34-week fetus with type I lissencephaly shows the absence of the cingulate sulcus from the expected location (arrow) on the medial hemispheric surface. This finding is considered abnormal at 34 weeks gestational age.
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Among the syndromes associated with type II lissencephaly, Walker-Warburg syndrome is most frequently detected at prenatal US. Imaging findings of ventriculomegaly (Figs 11a, 12a, 12b), abnormalities of the posterior fossa (cerebellum and brainstem) (Figs 11b, 12b), encephalocele (Fig 13a), and ocular abnormalities (cataract, retinal dysplasia [Fig 13b]) may allow early prenatal diagnosis (20,21). Ventriculomegaly is the most common finding in Walker-Warburg syndrome; it is reported in 93% of cases (22). The cranial and extracranial US findings associated with Walker-Warburg syndrome are listed in Table 3.
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Figure 11a. Walker-Warburg syndrome. (a) Axial US image of a 16-week fetus shows ventriculomegaly, which is evidenced by dangling choroid plexi (C). The wall of the near-field lateral ventricle (arrowhead) also is visible. (b) Axial US image at a level caudad to a shows a large defect (*), due to vermian agenesis, between the cerebellar hemispheres (arrows). Pathologic analysis of a postmortem specimen, obtained after delivery of the fetus at 19 weeks, showed cobblestone complex. There was a previous history of three stillborn fetuses with Walker-Warburg syndrome.
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Figure 11b. Walker-Warburg syndrome. (a) Axial US image of a 16-week fetus shows ventriculomegaly, which is evidenced by dangling choroid plexi (C). The wall of the near-field lateral ventricle (arrowhead) also is visible. (b) Axial US image at a level caudad to a shows a large defect (*), due to vermian agenesis, between the cerebellar hemispheres (arrows). Pathologic analysis of a postmortem specimen, obtained after delivery of the fetus at 19 weeks, showed cobblestone complex. There was a previous history of three stillborn fetuses with Walker-Warburg syndrome.
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Figure 12a. Walker-Warburg syndrome. (a) Axial US image of a 25-week fetus shows a dilated lateral ventricle (V) with posterior rupture (arrowhead); a small skin-covered occipital encephalocele (white arrow); and a flat appearance of the sylvian fissure (black arrow), which is abnormal at 25 weeks of gestation. Vermian hypoplasia (not shown) also was present. (b) Coronal US image at 35 weeks shows a dilated third ventricle (*), asymmetrically dilated frontal horns (V), an abnormal sylvian fissure (black arrow), and a small brainstem (white arrow). (c) Parasagittal T2-weighted SSFSE MR image at 27 weeks shows an irregular surface of the frontoparietal cortex (arrow) and a dilated ventricle (V) with irregular walls, a feature suggestive of subependymal heterotopia. (d) Sagittal T2-weighted SSFSE MR image at 27 weeks demonstrates the typical Z-shaped brainstem (white arrow) and hypoplastic vermis (black arrow). (e) Axial T2-weighted SSFSE MR image at 27 weeks shows asymmetry of the globes of the eyes (arrows), ventriculomegaly (V), and ventricular rupture (arrowhead).
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Figure 12b. Walker-Warburg syndrome. (a) Axial US image of a 25-week fetus shows a dilated lateral ventricle (V) with posterior rupture (arrowhead); a small skin-covered occipital encephalocele (white arrow); and a flat appearance of the sylvian fissure (black arrow), which is abnormal at 25 weeks of gestation. Vermian hypoplasia (not shown) also was present. (b) Coronal US image at 35 weeks shows a dilated third ventricle (*), asymmetrically dilated frontal horns (V), an abnormal sylvian fissure (black arrow), and a small brainstem (white arrow). (c) Parasagittal T2-weighted SSFSE MR image at 27 weeks shows an irregular surface of the frontoparietal cortex (arrow) and a dilated ventricle (V) with irregular walls, a feature suggestive of subependymal heterotopia. (d) Sagittal T2-weighted SSFSE MR image at 27 weeks demonstrates the typical Z-shaped brainstem (white arrow) and hypoplastic vermis (black arrow). (e) Axial T2-weighted SSFSE MR image at 27 weeks shows asymmetry of the globes of the eyes (arrows), ventriculomegaly (V), and ventricular rupture (arrowhead).
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Figure 12c. Walker-Warburg syndrome. (a) Axial US image of a 25-week fetus shows a dilated lateral ventricle (V) with posterior rupture (arrowhead); a small skin-covered occipital encephalocele (white arrow); and a flat appearance of the sylvian fissure (black arrow), which is abnormal at 25 weeks of gestation. Vermian hypoplasia (not shown) also was present. (b) Coronal US image at 35 weeks shows a dilated third ventricle (*), asymmetrically dilated frontal horns (V), an abnormal sylvian fissure (black arrow), and a small brainstem (white arrow). (c) Parasagittal T2-weighted SSFSE MR image at 27 weeks shows an irregular surface of the frontoparietal cortex (arrow) and a dilated ventricle (V) with irregular walls, a feature suggestive of subependymal heterotopia. (d) Sagittal T2-weighted SSFSE MR image at 27 weeks demonstrates the typical Z-shaped brainstem (white arrow) and hypoplastic vermis (black arrow). (e) Axial T2-weighted SSFSE MR image at 27 weeks shows asymmetry of the globes of the eyes (arrows), ventriculomegaly (V), and ventricular rupture (arrowhead).
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Figure 12d. Walker-Warburg syndrome. (a) Axial US image of a 25-week fetus shows a dilated lateral ventricle (V) with posterior rupture (arrowhead); a small skin-covered occipital encephalocele (white arrow); and a flat appearance of the sylvian fissure (black arrow), which is abnormal at 25 weeks of gestation. Vermian hypoplasia (not shown) also was present. (b) Coronal US image at 35 weeks shows a dilated third ventricle (*), asymmetrically dilated frontal horns (V), an abnormal sylvian fissure (black arrow), and a small brainstem (white arrow). (c) Parasagittal T2-weighted SSFSE MR image at 27 weeks shows an irregular surface of the frontoparietal cortex (arrow) and a dilated ventricle (V) with irregular walls, a feature suggestive of subependymal heterotopia. (d) Sagittal T2-weighted SSFSE MR image at 27 weeks demonstrates the typical Z-shaped brainstem (white arrow) and hypoplastic vermis (black arrow). (e) Axial T2-weighted SSFSE MR image at 27 weeks shows asymmetry of the globes of the eyes (arrows), ventriculomegaly (V), and ventricular rupture (arrowhead).
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Figure 12e. Walker-Warburg syndrome. (a) Axial US image of a 25-week fetus shows a dilated lateral ventricle (V) with posterior rupture (arrowhead); a small skin-covered occipital encephalocele (white arrow); and a flat appearance of the sylvian fissure (black arrow), which is abnormal at 25 weeks of gestation. Vermian hypoplasia (not shown) also was present. (b) Coronal US image at 35 weeks shows a dilated third ventricle (*), asymmetrically dilated frontal horns (V), an abnormal sylvian fissure (black arrow), and a small brainstem (white arrow). (c) Parasagittal T2-weighted SSFSE MR image at 27 weeks shows an irregular surface of the frontoparietal cortex (arrow) and a dilated ventricle (V) with irregular walls, a feature suggestive of subependymal heterotopia. (d) Sagittal T2-weighted SSFSE MR image at 27 weeks demonstrates the typical Z-shaped brainstem (white arrow) and hypoplastic vermis (black arrow). (e) Axial T2-weighted SSFSE MR image at 27 weeks shows asymmetry of the globes of the eyes (arrows), ventriculomegaly (V), and ventricular rupture (arrowhead).
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Figure 13a. Encephalocele and retinal nonattachment in Walker-Warburg syndrome (HARD±E syndrome). (a) Axial US image of the cranium in an 18-week fetus shows an encephalocele (arrow) that protrudes through an occipital bone defect. (b) Axial US image of the right orbit in a 35-week fetus shows a conical structure within the globe, a feature indicative of retinal nonattachment (arrow). The base of the abnormal retina faces the lens, and the apex points posteriorly toward the optic nerve. N = nose.
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Figure 13b. Encephalocele and retinal nonattachment in Walker-Warburg syndrome (HARD±E syndrome). (a) Axial US image of the cranium in an 18-week fetus shows an encephalocele (arrow) that protrudes through an occipital bone defect. (b) Axial US image of the right orbit in a 35-week fetus shows a conical structure within the globe, a feature indicative of retinal nonattachment (arrow). The base of the abnormal retina faces the lens, and the apex points posteriorly toward the optic nerve. N = nose.
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Prenatal Diagnosis with MR Imaging
MR imaging is very useful for detecting and confirming abnormal cortical development. Associated abnormalities of the corpus callosum, brainstem, and cerebellum are also well depicted on MR images (24,25). Less severe forms of lissencephaly may be more readily detected on MR images, but less severe forms of cortical dysplasia may not become evident until late in the third trimester or even postnatal life.
In Miller-Dieker syndrome, agyric cerebral cortex is seen with shallow sylvian fissures. These features give the brain the appearance of an hourglass or a figure-of-eight on axial images (Figs 8b, 9b). In Walker-Warburg syndrome, the cerebral cortex shows combined agyria and pachygyria (Fig 12c) as well as polymicrogyria with a pebbled surface (the cobblestone cortex). Specific features of brainstem hypoplasia—in particular, a Z-shaped brainstem or notched pons—can alert the radiologist to the possibility of congenital muscular dystrophy (26). These findings can be seen best on sagittal MR images (Fig 12d). Other findings on MR images include cerebellar hypoplasia (mainly involving the vermis) (Fig 12d); enlarged ventricles and occasional ventricular rupture (Fig 12e); corpus callosum dysgenesis; white matter abnormalities; and ocular abnormalities (Fig 12e) (27,28).
Genetic Evaluation
So far, six genes associated with type I lissencephaly have been identified (Table 4). Miller-Dieker syndrome is associated with a deletion at the 17p13.3 locus. Deletions of LIS1, YWHAE, CRK, and probably other genes result in Miller-Dieker syndrome, which consists of the most severe form of lissencephaly, facial dysmorphism, and other abnormalities (29–31). Isolated lissencephaly sequence is the result of either a mutation or a deletion of LIS1. Most cases of Miller-Dieker syndrome and isolated lissencephaly sequence are sporadic. However, approximately 20% of patients with Miller-Dieker syndrome inherited a genetic deletion from a parent (32). In our series of seven fetuses with a diagnosis of Miller-Dieker syndrome, three (40%) of the seven cases were familial (18). Therefore, parents of affected fetuses should be offered chromosomal analysis to rule out parental chromosomal rearrangements. When agyria is detected at fetal US and MR imaging, Miller-Dieker syndrome can be confirmed with a fluorescence in situ hybridization analysis by using a DNA probe that is specific for the LIS1 gene to detect a deletion at chromosome 17p13.3. When X-linked lissencephaly is identified in a proband, MR imaging and genetic analysis can be performed in the mother to determine whether the mutation is inherited.
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Abstract
LEARNING OBJECTIVES
