American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 154C:120 132 (2010)

A R T I C L E

Neuroimaging Advances in Holoprosencephaly: Rening the Spectrum of the Midline Malformation

JIN S. HAHN* AND PATRICK D. BARNES
Holoprosencephaly (HPE) is a complex congenital brain malformation characterized by failure of the forebrain to bifurcate into two hemispheres, a process normally completed by the fth week of gestation. Modern highresolution brain magnetic resonance imaging (MRI) has allowed detailed analysis of the cortical, white matter, and deep gray structural anomalies in HPE in living humans. This has led to better classication of types of HPE, identication of newer subtypes, and understanding of the pathogenesis. Currently, there are four generally accepted subtypes of HPE: alobar, semilobar, lobar, and middle interhemispheric variant. These subtypes are dened primarily by the degree and region of neocortical nonseparation. Rather than there being four discrete subtypes of HPE, we believe that there is a continuum of midline neocortical nonseparation resulting in a spectrum disorder. Many patients with HPE fall within the border zone between the neighboring subtypes. In addition, there are patients with very mild HPE, where the nonseparation is restricted to the preoptic (suprachiasmic) area. In addition to the neocortex, other midline structures such as the thalami, hypothalamic nuclei, and basal ganglia are often nonseparated in HPE. The cortical and subcortical involvements in HPE are thought to occur due to a disruption in the ventral patterning process during development. The severity of the abnormalities in these structures determines the severity of the neurodevelopmental outcome and associated sequelae.
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KEY WORDS: holoprosencephaly; MRI; brain malformation; neuroimaging; development; midline; telencephalon; diencephalon; prosencephalon; preoptic area

How to cite this article: Hahn JS, Barnes PD. 2010. Neuroimaging advances in holoprosencephaly: Rening the spectrum of the midline malformation. Am J Med Genet Part C Semin Med Genet 154C:120132.

INTRODUCTION
Holoprosencephaly (HPE) is a complex congenital brain malformation characterized by failure of the forebrain to bifurcate into two hemispheres, a process normally complete by the fth week of gestation [Golden, 1999]. Modern high-resolution brain magnetic resonance imaging (MRI) has allowed detailed analysis of the cortical, white matter, and deep gray structural anomalies in HPE. This has led to better

classication of types of HPE, identication of newer subtypes, and understanding of the pathogenesis.

structures affects parts of the telencephalon and diencephalon. Sometimes

DEFINITION AND CLASSIFICATION

The sine qua non feature of HPE is an incomplete separation of the cerebral hemispheres that results in lack of cleavage, or nonseparation, of midline structures. As the name HPE implies, these nonseparated prosencephalic

Jin Hahn, M.D. Professor of Neurology and Pediatrics, Stanford University School of Medicine and Lucile Packard Childrens Hospital. Medical Director, Stanford Carter Center for Research in Holoprosencephaly and Related Brain Malformations. Research interests: brain development and malformations, prenatal neurological consultation and fetal MRI, neonatal neurology. Patrick Barnes, M.D. Professor of Radiology, Stanford University School of Medicine. Chief, Section of Pediatric Neuroradiology; Director, Pediatric MRI and CT, Lucile Packard Childrens Hospital at Stanford Research interests: Advanced imaging, including magnetic resonance imaging, of injury to the developing central nervous system; including fetal, neonatal, infant and young child; and, including nonaccidental injury (e.g., child abuse). Grant sponsor: Carter Centers for Brain Research in Holoprosencephaly and Related Malformations; Grant sponsor: Don and Linda Carter Foundation; Grant sponsor: CrowleyCarter Foundation. *Correspondence to: Jin S. Hahn, Department of Neurology, Stanford University Medical Center, 300 Pasteur Drive, Room A343, Stanford, CA 94305-5235, USA. E-mail: jhahn@stanford.edu DOI 10.1002/ajmg.c.30238 Published online 26 January 2010 in Wiley InterScience (www.interscience.wiley.com)

The sine qua non feature of HPE is an incomplete separation of the cerebral hemispheres that results in lack of cleavage, or nonseparation, of midline structures. As the name HPE implies, these nonseparated prosencephalic structures affects parts of the telencephalon and diencephalon.
these abnormal midline structures are described as being fused, but it should be kept in mind that appearance of fusion results from abnormal bifurcation of those structures, rather than paired

2010 Wiley-Liss, Inc.

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structure actively merging. HPE has traditionally been classied according to the DeMyers three grades of severity: alobar, semilobar, and lobar [DeMyer, 1987]. In addition to these classic forms, a milder subtype of HPE, the middle interhemispheric (MIH) variant or syntelencephaly has been characterized [Lewis et al., 2002; Simon et al., 2002]. The neuroimaging ndings of these types are provided below and summarized in Table I. See Marcorelles and Laquerriere [2010] for a review of HPE neuropathology. Alobar HPE In the most severe form, alobar HPE, there is complete or nearly

complete lack of separation of the cerebral hemispheres with a single midline forebrain ventricle (a crescent shaped monoventricle), which often communicates with a dorsal cyst (Fig. 1). The cerebral holosphere usually has the appearance of a pancake-like mass of tissue in the rostral-most portion of the calvarium. The posterior aspect of the cerebrum is shaped like a horseshoe with the posterior-dorsal rim composed of a thin, cyst-like membrane [Golden, 1999]. This membrane is the posterior roof of the monoventricle. When the dorsal cyst is smaller, the posterior-dorsal rim is located more posteriorly and the holosphere may have a cup-like appearance (Fig. 2) [DeMyer, 1987]. The structures of the

temporal axis are formed, but the temporal limbs of the choroid ssures are splayed open [Takahashi et al., 2004]. The interhemispheric ssure, falx cerebri, and corpus callosum are completely absent. The basal ganglia and hypothalamic and thalamic nuclei often lack separation resulting in absence of the third ventricle [Simon and Barkovich, 2001]. At times, a mass of deep gray matter is present with poorly differentiated striatum and thalamus (Fig. 1B) and may include parts of the mesencephalon. This mass may be attached to the holosphere by a small anterior midline hinge of tissue that lacks corticospinal, corticothalamic, and thalamocortical tracts [Muenke, 1995]. Olfactory bulbs and tracts are absent [Yamada et al., 2004].

TABLE I. Neuroimaging Features of Various Types of HPE Alobar Cortical nonseparation Corpus callosum Diffuse (holosphere) Absent Frontal Rostrum, genu, and body absent. Splenium present Present posteriorly only Semilobar Lobar Basal frontal Rostrum and genu absent. Anterior body variably present. Splenium present Hypoplastic anteriorly and present posteriorly Rudimentary anterior horns. Third ventricle formed Absent Absent or dysplastic Usually fully separated Variable degree of fusion MIH Posterior frontal and parietal Body absent; genu variably present. Splenium present Absent in the posterior frontal and parietal region Normal or hypoplastic anterior horns. Third ventricle formed Present in 1/4 Absent Fused in 1/3 to 1/2 Separated

IHF and Falx

Ventricles

Completely absent anteriorly and posteriorly Monoventricle communicating widely with dorsal cyst Usually present Absent Often fused Often fused (may form single mass with thalami) Always fused to some degree (100%) Often absent

Dorsal cyst Septum pellucidum Thalamus Basal ganglia

Anterior horns absent. Posterior horns present. Small third ventricle Variably present Absent Partial fusion Partial fusion (especially head of caudate) Very often fused to some degree (98%) Anteriorly and medially displaced (wide sylvian ssure) with fused frontal lobe Occasional broad gyri with too few sulci Azygous anterior cerebral artery

Hypothalamus Sylvian ssure

Cortical dysplasia and heterotopic gray matter Cerebral vasculature

Frequent presence of diffuse broad gyri with too few sulci Rete of vessels branching from the internal cerebral arteries

Often fused to some degree (83%) Anteriorly and medially displaced (wide sylvian ssure) with small frontal lobes Rare midline subcortical heterotopias in frontal regions Azygous anterior cerebral artery

Separated Often abnormally connected across the midline over the vertex Very common

Azygous anterior cerebral artery

Based on Simon et al. [2000, 2002], Plawner et al. [2002].

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Figure 1. MRI of a 1-day-old neonate with alobar HPE. Sagittal T1-weighted image (A) shows absence of corpus callosum and a monoventricle (MV) that communicates with the dorsal cyst. Axial T1-weighted image at the level of the thalami (B) demonstrates large central gray mass that consists of thalamic nuclei and basal ganglia (arrowheads). At a more rostral level axial T1-weighted image (C) shows a crescentic shaped MV surrounded by a attened holosphere and large dorsal cyst (DC) posteriorly.

Affected children with alobar HPE are typically abnormal from the neonatal period and present with hypotonia and seizures. Midline craniofacial malformations including hypotelorism, premaxillary hypogenesis and cleft, and hypoplastic nose are often present. A large dorsal cyst may result in hydrocephalus and macrocephaly. Otherwise, the head is microcephalic.

Semilobar HPE In semilobar HPE, the anterior hemispheres fail to separate, while some portions of the posterior hemispheres show separation (Fig. 3). The noncleaved frontal lobes are usually small.

In semilobar HPE, the anterior hemispheres fail

to separate, while some portions of the posterior hemispheres show separation. The noncleaved frontal lobes are usually small.

Figure 2. MRI of a 5-day-old newborn with alobar HPE. Sagittal T1-weight image (A) shows a holosphere that takes up more than half of the cranial vault. Corpus callosum is not visualized. The ventricular system is composed of a single midline monoventricle (MV) that communicates openly with the posteriorly positioned dorsal cyst (DC). Axial T2-weighted image (B) shows lack of separation of the hemispheres. The holosphere extends further posteriorly (compared to the patient in Fig. 1) forming a cup-like holosphere. The caudate and lentiform nuclei are not well differentiated and are fused in the midline (white arrow). Coronal T2-weighted image (C) shows a continuity of gray matter in the midline without an interhemispheric ssure. The thalamic nuclei are partially fused (black arrow).

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Figure 3. MRI of a 7-month-old infant girl with semilobar HPE. Sagittal T1-weighted image (A) demonstrates absence of the genu and body of the corpus callosum, but presence of the splenium (white arrowheads). Axial T2-weighted image (B) shows absence of interhemispheric ssure anteriorly. The posterior hemispheres are well separated and the posterior horns of the lateral ventricles are well formed. The head of the caudate are nonseparated and the thalami are partially separated. The third ventricle is abnormal and the frontal horns are absent. Coronal T2-weighted image (C) at the level of the thalami shows a shallow interhemispheric ssure (black arrowheads) and fusion of cortical matter at the midline.

The frontal horns of the lateral ventricle are absent, but posterior horns and trigones are present. The septum pellucidum is absent. The corpus callosum is absent anteriorly, but the splenium of the corpus callosum is present. The anterior extent of the corpus callosum development also correspond with the anterior extent of the interhemispheric ssure formation [Simon and Barkovich, 2001]. On imaging studies, some portions of the posterior interhemispheric ssure, falx cerebri, and splenium of the corpus callosum can be identied. The hippocampal formation in the temporal lobes appears normal and the temporal limbs of the choroid ssures are closed [Takahashi et al., 2004]. The deep gray nuclei are incompletely separated and can usually be identied as discrete structures, usually resulting in a small third ventricle [Simon et al., 2000]. The head of the caudate nuclei is often nonseparated. Dorsal cysts are sometimes seen in semilobar HPE, especially when there is nonseparation of the thalamic nuclei. The olfactory bulbs are either absent or hypoplastic. Facial malformations are usually mild or absent. The head is microcephalic, unless a large dorsal cyst and hydrocephalus are present. Patients often have severe motor abnormalities in-

cluding dystonia, choreoathetosis, and spasticity, as well as developmental delay.

Middle Interhemispheric Variant (Syntelencephaly) MIH is a subtype of HPE that presents clinically as a milder phenotype [Simon et al., 2002]. The neuroimaging features of MIH subtype are different from classic HPE. Unlike classic HPE, where the most severely nonseparated region of the hemispheres is the basal forebrain, in MIH the posterior frontal and parietal lobes fail to separate (Fig. 5). The poles of the frontal and occipital lobes are well separated in MIH. The genu and splenium of the corpus callosum appear normally formed, but the callosal body is absent. The hypothalamus and lentiform nuclei appear normally separated in MIH patients, but the caudate nuclei and thalami are incompletely separated in many patients [Simon et al., 2002]. The sylvian ssures in most patients are oriented nearly vertically and were abnormally connected across the midline over the vertex of the brain [Simon et al., 2002]. Approximately two-thirds of the MIH patients have either subcortical heterotopic gray matter or cortical dysplasia. Abnormally thick cortex lining the anterior interhemispheric ssure was often present and was contiguous across the midline. As in other types of HPE, the anterior vascu-

Lobar HPE In lobar HPE, a milder phenotypic form, the cerebral hemispheres are fairly well developed and separated, while only the most rostral/ventral aspects of the frontal neocortex are nonseparated (Fig. 4). Again, the corpus callosum is absent in the region affected (usually rostrum and genu). The posterior half of the corpus callosum (including the splenium and posterior body) is present. Rudimentary formation of the frontal horns is usually present. The third ventricle is fully formed. The interhemispheric ssure and falx cerebri are present anteriorly, although these structures are hypoplastic owing to the frontal lobe fusion [Simon and Barkovich, 2001]. The thalamic nuclei may be fully separated, although an enlarged massa intermedia may be present. A dorsal cyst is usually absent. Olfactory bulbs and tracts may be present, although they are usually hypoplastic. An azygous anterior cerebral artery (ACA) is usually present in the anterior IHF.

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Figure 4. MRI of a 19-month-old boy with lobar HPE. Sagittal T1-weighted image (A) demonstrates the presence of posterior body and splenium of the corpus callosum (arrowheads), but the genu is not developed and the anterior body is very hypoplastic. Axial T2weighted image (B) shows that the anterior and posterior interhemispheric ssures (IHFs) are present (arrows). The cerebral hemispheres that are fairly well separated both anteriorly and posteriorly, but there is abnormal gray matter continuous across the midline anteriorly (curved arrow). An azygous anterior cerebral artery ow void is present in the anterior IHF. The fontal horns are rudimentary. Coronal SPGR image (C) shows failure of complete separations of the frontal lobes across the interhemispheric ssure (curved arrow) and continuous gray matter in the basal frontal regions (arrow).

lature is abnormal with an azygous ACA noted in all patients. Patients usually have normal or large intraocular distances (hypertelorism). Septo-Optic Dysplasia and HPE Some of the patients with lobar HPE may fall within the spectrum of septooptic dysplasia [Barkovich et al., 1989]. In these patients, there is complete absence of the septum pellucidum

and hypoplasia of the optic nerves and chiasm. These patients have visual

Some of the patients with lobar HPE may fall within the spectrum of septo-optic dysplasia. In these patients, there is complete absence of the

septum pellucidum and hypoplasia of the optic nerves and chiasm.

impairment and hypothalamic pituitary axis abnormality resulting in endocrinopathies. Careful examination of the MRI images will show anterior callosal dysgenesis and hypothalamic or preoptic area dysgenesis or fusion (Fig. 6).

Figure 5. MRI of a child with an initial diagnosis of septo-optic dysplasia and diabetes insipidus taken at 1 month of age. Sagittal T1weight image (A) shows absence of rostrum and genu of the corpus callosum (arrowheads). Axial T2-weighted image (B) shows absence of the septum pellucidum and hypoplastic frontal horns. Coronal T1-weighted image (C) shows absence of the septum pellucidum and the anterior corpus callosum. The hypothalamus and basal structures appear to be fused and the third ventricle is not well formed. The optic chiasm was noted to be hypoplastic and was given diagnosis of septo-optic dysplasia. She had optic nerve hypoplasia, visual impairment, multiple endocrine deciencies, and diabetes insipidus. At 2.5 years of age lobar HPE was diagnoses based on this MRI.

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anterior falx. Generally, the patient is classied as semilobar if the frontal lobes are greater than 50% fused and lobar if less than 50% fused. However, this is a somewhat arbitrary criterion, one that is often difcult to quantitate. Presence of a fully developed third ventricle, some frontal horns, and posterior half of the corpus callosum (posterior body and splenium) would favor classication as lobar HPE. Continuum between MIH and lobar At times there may be features of both MIH and lobar HPE. The anterior and posterior poles of the hemisphere are separated but there is nonseparation of the perirolandic cortex (as seen in MIH), as well as, the basal frontal lobes (as seen in lobar) (Fig. 7). In MIH, the corpus callosum is dysplastic most often in the region of the body, whereas in lobar HPE, the genu and rostrum are most often affected. In patients who fall in the borderline, the corpus callosum dysgenesis may involve all of these callosal areas (excluding the splenium).
Figure 6. MRI of a 2-year-old girl with MIH. Midsagittal T2-weighted image (A) shows the presence of genu and splenium of the corpus callosum (white arrowheads). The body of the corpus callosum is absent in the region of nonseparated hemispheres (white curved arrow). Coronal inversion-recovery image (B) at level of lentiform nuclei demonstrate continuity of the gray matter (black arrowheads) and absent septum pellucidum. Heterotopic gray matter is present in midline at the roof the lateral ventricle. Axial FLAIR image (C) shows continuity of gray matter anterior to the genu of corpus callosum and absent septum pellucidum. At a higher level, axial FLAIR image (D) shows anteriorly displaced sylvian ssures with abnormal gray matter crossing the midline.

Minimal Forms of HPE We have identied several patients with a minimal form of HPE with abnormal midline fusion limited to the preoptic area (involving the suprachiasmic region and anterior hypothalamus) or the septal region (subcallosal region) (Fig. 8). These patients have no or minimal fusion of the frontal neocortex. The fornices are often thickened and dysplastic and the anterior commissure may also be maldeveloped. An azygous ACA is often present. These patients are often brought to imaging because of subtle craniofacial malformation such as single median maxillary central incisor (SMMCI) and congenital nasal pyriform aperture stenosis (CNPAS), endocrinopathies, or mild developmental delays. Classifying these minimal patients as HPE may be controversial. Many who study HPE consider the presence of fornix, septum, and anterior commissure to essentially exclude the diagnosis of HPE, especially when the two cerebral hemispheres are completely

Without evidence of nonseparation in these regions, the patient should be classied as having septo-optic dysplasia only, not HPE. Spectrum of Hemispheric Nonseparation in HPE The classication of classic HPE based on the degree of hemispheric nonseparation falls within a spectrum. DeMyer [1987] brought attention to this spectrum when he stated, from the holospheric brain with no hint of an interhemispheric ssure, the spectrum of the malformation extends in unbroken continuity through intermediate and minimal stages. Because of this

continuum, neuroradiologists have found categorizing an individual patient into one of the three classic forms to be challenging at times [Simon and Barkovich, 2001], particularly in milder subtypes. We also believe that in HPE there is a continuum of abnormalities in the degree of hemispheric nonseparation. Continuum between semilobar and lobar HPE For example, the precise distinction between lobar and semilobar HPE is difcult in some patients, as there is a continuum of nonseparation of the frontal lobes and development of the anterior interhemispheric ssure and

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Figure 7. MRI of 20-month-old girl with features of lobar HPE and MIH. Axial T2-weighted image (A) shows small underdeveloped frontal horns and absence of septum pellucidum. Gray matter band and azygous anterior cerebral artery are noted in midline in the shallow anterior interhemispheric ssure. Coronal T2-weighted image (B) shows large midline fusion of the frontal lobes anteriorly (arrowheads). Coronal T2-weighted image (C) further posteriorly at level of anterior thalami shows midline seam of gray matter (arrowheads).

separated (i.e., absence of neocortical fusion). Nevertheless, both the preoptic area and the septal region are telencephalic structures (with the former being closely related in structure to the hypothalamus, a diencephalic structure). Therefore, the nonseparation of these midline structures would be consistent with the ventral patterning defect seen in classic HPE. We believe that these patients represent the mildest end of

the spectrum of HPE. These patients are not microforms of HPE, which by denition exclude brain involvement.

OTHER BRAIN STRUCTURES INVOLVED IN HPE

In addition to the hemispheric nonseparation, attention should also be paid to other midline structures of the brain.

Several neuroimaging studies of a large cohort of HPE patients [Simon et al., 2000, 2001, 2002; Barkovich et al., 2002a,b] have provided a grading system for various involved brain structures of HPE. This has allowed the correlation of imaging ndings and clinical characteristics [Lewis et al., 2002; Plawner et al., 2002] and led to a better understanding of the embryological derangements that lead to HPE.

Figure 8. MRI of a 10-year-old boy with learning disabilities, single median maxillary central incisor, congenital nasal pyriform aperture stenosis, and endocrinopathies. T1-weighted midsagittal image (A) shows hypoplasia of the rostrum of corpus callosum and a rectangular area of abnormality in the subcallosal region, anterior to the hypothalamic region (white arrowheads). The dysplastic appearing fornix is anterior to this region (white arrows). T2-weighted axial image (B) shows well-developed anterior and posterior interhemispheric ssures and an azygous anterior cerebral artery ow void in the interhemispheric ssure. There is an area of midline fusion just anterior to the anterior commissure, which appear as a dark bow-like band (white arrowheads). Further anterior to this region is the dysplastic fornix (white arrows). Coronal SPGR image (C) slight anterior to the anterior commissure shows the dysplastic fornix (white arrows) traveling below the septum pellucidum and inferior to that the area of midline fusion (white arrowheads).

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Deep Gray Nuclei The deep gray nuclear structures and diencephalon are often profoundly affected in many patients with HPE. A neuroimaging study of 57 classic HPE patients (43 MRI studies and 14 highquality CT studies) revealed that the hypothalamus and caudate nuclei were the most commonly nonseparated deep gray structures in HPE [Simon et al., 2000]. Nearly all patients (99%) with classic HPE had some degree of hypothalamic nonseparation (Fig. 9). The caudate nuclei were not fully separated in 96% of the patients. The thalami were

Nearly all patients (99%) with classic HPE had some degree of hypothalamic nonseparation. The caudate nuclei were not fully separated in 96% of the patients.

In 27% of the patients, the mesencephalon showed some degree of nonseparation, implying that in a large proportion of patients the rhombencephalon is also disturbed during development. The midbrain involvement may be seen pathologically a failure of two distinct paired superior and inferior colliculi to form, continuity of the oculomotor nuclei across the midline, and aqueductal atresia or stenosis [Vogel et al., 1990; Sarnat and Flores-Sarnat, 2001]. In 11% of the HPE patients, a single deep gray nuclear mass without discrete basal ganglia, thalami, and mesencephalon was noted (Fig. 1B). The pattern of deep gray nuclei abnormalities, in particular the universal involvement of the hypothalamus, supports the theory that a lack of induction of the most rostral aspects of the embryonic oor plate is the cause of classic HPE. The nding of mesencephalic abnormalities implies that in the abnormal development in HPE, the rostral-caudal gradient at times extends more caudally beyond the prosencephalon. Midline Dorsal Cyst Dorsal cysts are more often present in alobar HPE (92%), compared to semilobar HPE (28%) and lobar HPE (9%)

[Plawner et al., 2002] (Figs. 1 and 2). The presence of dorsal cysts strongly correlates with the degree nonseparation of the thalami [Simon et al., 2001; Plawner

Dorsal cysts are more often present in alobar HPE (92%), compared to semilobar HPE (28%) and lobar HPE (9%). The presence of dorsal cysts strongly correlates with the degree nonseparation of the thalami
et al., 2002]. It is hypothesized that the nonseparated thalamus physically blocks egress of CSF from the third ventricle. The egress of the CSF through the path of least resistance, which is the thin posterior wall of the third ventricle in the suprapineal recess, results in expansion of the posterodorsal portion of the ventricle to form the dorsal cyst. Supporting this theory, hydrocephalus is often, but not always, noted in association with dorsal cysts [Simon and Barkovich, 2001; Plawner et al., 2002]. Two-fth of HPE patients with dorsal cyst require CSF shunting procedure [Plawner et al., 2002]. Additional abnormalities of the cerebral aqueduct of Sylvius, such as atresia or stenosis that have been found in HPE on neuropathologic examination [Vogel et al., 1990] may also contribute to the obstruction of CSF ow and requirement for shunting. The gross morphologic descriptions of the holosphere as pancake, cup, or ball shape is a reection of the size of the dorsal cyst. Smaller dorsal cysts may remain stable without causing hydrocephalus, or disappear after a CSF shunting procedure. Occasionally, the dorsal cyst herniates through the anterior fontanelle to form a vertex encephalocele that is unique in HPE [Sarnat and Flores-Sarnat, 2001]. The dorsal cyst of HPE is similar in appearance to the interhemispheric cyst

the least frequently involved of the deep gray nuclei, showing nonseparation in 67%. Abnormal orientation of the long axis of the thalamus (outside of 308 458) was seen in 71% of the patients.

Figure 9. Hypothalamic involvement in HPE. Coronal T2-weighted image (A) in 16-year-old girl with lobar HPE demonstrates complete separate of the hypothalamus with fully formed third ventricle. Coronal T2-weighted FSE image (B) in a neonate with semilobar HPE reveals complete nonseparation of the hypothalamus and absent third ventricle.

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associated with agenesis of the corpus callosum [Young et al., 1992]. The latter is frequently misdiagnosed as HPE, but is distinguished by normal cleavage of the basal forebrain structures. Differentiating these can be especially difcult when the abnormal brain anatomy is further distorted by hydrocephalus. Denitive diagnosis in these patients often requires a repeat MRI after decompression. Cortical Gyral Abnormalities In a neuroimaging study of 96 patients with classic HPE, the cortical thickness was normal in all patients, and gyral/sulcal sizes were normal in 83% [Barkovich et al., 2002a]. Diffuse dysplastic cortex and broad gyri with too few sulci may be present is some patients with HPE. Although the cortex may appear too thick, as in pachygyria, the measured cortical thickness is normal. This gyral pattern is more common in alobar (seen in 8/96) but can also be seen in semilobar (Fig. 10). Subcortical heterotopia occur in a small percentage of patients with classic HPE (only 4 of 96 patients in study by Barkovich et al. [2002a]), and often consist of large masses that crossed the midline in the noncleaved regions (Fig. 11A,B). Large midline mass of

subcortical dysplastic cortex have been noted in rare patients (Fig. 11C) which some authors refer to as brain in brain malformation [Widjaja et al., 2007]. These patients often have lobar HPE or MIH, and develop severe localizationrelated epilepsy. In the most severe patient with alobar HPE, no sylvian ssure can be identied. In less severe forms the sylvian ssures are displaced more anteriorly and medially as HPE reecting the degree of frontal lobe development [Barkovich et al., 2002a]. The degree of the displacement of the sylvian ssures (as measured by the sylvian angle) correlated strongly with the severity of classic HPE (alobar > semilobar > lobar) and with the degree of abnormal frontal lobe development. White Matter Abnormalities MRI studies of the white matter in HPE have focused on callosal abnormalities [Simon and Barkovich, 2001; Simon et al., 2002]. The degree of callosal dysgenesis correlates with the severity of the midline hemispheric fusion. In addition in classic HPE, there is a delay in myelination of the white matter maturity [Barkovich et al., 2002b]. Patient with MIH had normal myelination development.

Diffusion tensor imaging (DTI) and tractography techniques have been applied to analyze white matter tracts abnormalities in HPE [Albayram et al., 2002; Rollins, 2005]. In patients with alobar HPE, the cortico-ponto-spinal tracts were absent bilaterally, conrming the ndings from prior neuropathological studies [Kobori et al., 1987]. In most patients with less severe types of HPE, the corticospinal tracts were present bilaterally. HPE type and neurodevelopmental score correlated strongly with cortico-ponto-spinal tracts and middle cerebellar peduncle dimensions. Thickened dysplastic fornices have been noted with DTI tractography in a patient with semilobar HPE [Rollins, 2005]. These ndings demonstrate that analysis of white matter tracts in HPE using DTI adds complementary information to traditional MRI analysis. Other Cerebral Anomalies On rare occasions, other cerebral anomalies may be associated with HPE including schizencephaly, Dandy Walker complex, Chiari malformations, and various encephaloceles. Other posterior fossa abnormalities such as rhombencephalosynapsis, in which there is abnormal nonseparation of the cerebellar hemispheres, are also occasionally seen in HPE. A rare patient of diffuse polymicrogyria in a patient with MIH has been reported [Takanashi et al., 2003]. Vascular Anomalies The anterior circulation vasculature is often abnormal in HPE. In more severe types (alobar and semilobar) of HPE, there is a lack of formation of normal middle and anterior cerebral arteries, being replaced by a rete of vessels arising from the internal carotid and basilar arteries. In less severe patients, including MIH, the arterial system is nearly normal but an azygous, or unpaired, ACA is nearly always noted [Simon and Barkovich, 2001]. We also noted an azygous ACA in our patients with the minimal form of HPE involving the preoptic/septal regions.

Figure 10. MRI of a 3-day-old female infant with semilobar HPE. Axial (A) and coronal (B) T2-weighted images shows very simplied gyral pattern with broad gyri and too few sulci. The images also show fusion of the thalamic nuclei and large monoventricle without a clear dorsal cyst.

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Figure 11. A,B: MRI of a 2-year-old girl with lobar holoprosencephaly and subcortical heterotopia. Axial T2-weighted (A) and oblique coronal STIR (B) images show large subcortical gray matter heterotopia (white arrowheads) located in the right frontal lobe white matter in addition to midline gray matter fusion in the anterior interhemispheric ssure. This patient also had refractory epilepsy. C: T2-weighted coronal MRI of a 1.5-year-old patient with MIH and subcortical heterotopia consisting of large infolding dysplastic cortex (black arrowheads). This child also had severe localization-related epilepsy. D: Coronal spoiled gradient-recalled image in a patient with semilobar HPE shows heterotopia gray at the roof of the monoventricle (white arrowheads).

Neuroimaging Techniques and Systematic Method of Review To properly interpret the neuroimaging study of a patient suspected of having HPE, a high-resolution MRI scans that include thin-section image sequences in three orthogonal planes (axial, sagittal, and coronal) are preferred. T2-weight axial and coronal images are preferred.

sequences in three orthogonal planes (axial, sagittal, and coronal) are preferred. T2-weight axial and coronal images are preferred.

To properly interpret the neuroimaging study of a patient suspected of having HPE, a high-resolution MRI scans that include thin-section image

The study should also include a volumetric dataset (three-dimensional spoiled gradient-echo sequences), which provides good gray-white matter differentiation and permits reformatting in other planes and volumetric analyses [Simon and Barkovich, 2001].

To determine the type of HPE, careful assessment of the telencephalon is performed. Close attention is paid to the presence of anterior and posterior interhemispheric ssures and the extent of nonseparation of the two hemispheres. In addition, the basal ganglia, thalamic nuclei, hypothalamus, pituitary gland, and mesencephalon are analyzed for degree of nonseparation or dysgenesis. Other structures that are scrutinized include the morphology of the ventricular system and dorsal cyst, cortical malformations, subcortical heterotopia, sylvian ssure development, optic nerves and chiasm, and olfactory bulbs and tracts. The posterior fossa should also be examined carefully for abnormalities, including aqueductal dysgenesis, Dandy Walker complex, Chiari malformations, cerebellar abnormalities, and other brainstem abnormalities. Extracerebral structures that also warrant review are the presence of an SMMCI, CNPAS, premaxillary clefts, other midline clefts, and distance between the eyes (for hypo- or hypertelorism). When these extracerebral anomalies are found, careful attention should be paid attention to the preoptic area and septal region for minimal forms of HPE. Neuroimaging evaluation of the brain in HPE may be challenging in infants because of the inherent small brain size and immature myelination. Follow-up imaging after a period of brain growth may be required. Difculties in assessment also occur when hydrocephalus distorts underlying brain structures [Simon and Barkovich, 2001]. Denitive diagnosis in these patients may require repeat MRI after ventriculoperitoneal shunting. Ideally, a pediatric neuroradiologist with experience in brain malformations should review the imaging studies. Approximately 1/5 to 1/3 of the imaging studies referred to our centers for HPE fail to meet the HPE neuroimaging criteria [Stashinko et al., 2004; Hahn et al., 2008]. The ultimate diagnoses given to these studies include septooptic dysplasia, absent septum pelludicum with schizencephaly, agenesis of corpus callosum, or callosal agenesis with interhemispheric cyst (CAIHC).

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CAIHC type 1b is frequently misdiagnosed as HPE, but is distinguished by normal cleavage of the neocortical structures. The dorsal cyst of HPE

CAIHC type 1b is frequently misdiagnosed as HPE, but is distinguished by normal cleavage of the neocortical structures.

is similar in appearance to the interhemispheric cyst associated with CAIHC type 1b (Fig. 12) [Young et al., 1992; Barkovich et al., 2001]. The thalamic nuclei may be nonseparated in some patients with CAIHC, thus creating a blockage of CSF egress. Some authors refer to this malformation as holodiencephaly, meaning that the diencephalon, but not the telencephalon, is abnormally nonseparated. In absence of some degree of neocortical or preoptic area nonseparation, these patients should not be diagnosed with HPE. Nevertheless, patients with thalamic fusion may share similar pathogenetic mechanisms involved in HPE, and further studies are needed to understand

the boundaries and continuities of midline malformations. Three-dimensional MRI with reconstruction may provide complementary anatomic information that is not apparent from conventional MRI [Takahashi et al., 2003; Takahashi et al., 2004]. In semilobar HPE three-dimensional reconstructions reveal a rostrocaudally aligned midline gray matter seam that extends from the suprachiasmatic hypothalamus to a caudally positioned diminutive body and splenium of the corpus callosum [Takahashi et al., 2003]. In the rostral to caudal direction, the interhemispheric ssure also transitions from being absent, to a shallow but deepening zone, and nally to a zone where the ssure is at full depth. At this full depth zone, the midline gray matter is continuous with the neocortex of the cerebral surface. Caudal to the seam, the telencephalic structures are normally separated (between the right and left hemispheres) and the seam is replaced by the posterior corpus callosum. DTI has also been studied in patients with other types of HPE and is discussed in the White Matter Abnormality section above. Fetal Neuroimaging Prenatal ultrasounds have been used to detect the CNS and facial abnormal-

ities of severe HPE as early as the rst trimester [Filly et al., 1984; Nyberg et al., 1987; Tongsong et al., 1999]. Failure to identify the characteristics of the developing choroid plexuses (buttery sign) during the rst trimester may be a sensitive indicator of HPE [Sepulveda et al., 2004]. In alobar and semilobar HPE, prenatal diagnosis can readily be made by ultrasound [Peebles, 1998]. The sensitivity of ultrasonography for detection of milder forms of HPE (lobar and MIH) may be low, since in these forms the anterior and posterior interhemispheric ssures are present and the characteristic dorsal cyst of HPE is often absent. In our experience, prenatal ultrasonography had low sensitivity. Although prenatal ultrasound was performed in 93% of 104 HPE patients (weighted toward less severe type), prenatal diagnosis was made in only 22% [Stashinko et al., 2004]. Fetal MRI will provide better characterization of the malformations [Sonigo et al., 1998]. Modern ultrafast MRI techniques reduce movement artifacts signicantly and are ideal for fetal imaging (Fig. 13). Fetal MRI has been used to diagnose various forms of HPE including alobar, semilobar, lobar [Wong et al., 2005], and MIH variant [Pulitzer et al., 2004; Picone et al., 2006]. Other midline anomalies, such as agenesis of corpus callosum, CAIHC,

Figure 12. MRI in a 15-month-old female infant with thalamic fusion (holodiencephaly) and interhemispheric cyst. T2-weighted axial (A) and coronal (B) images show thalamic fusion (black arrows) and a very large interhemispheric cyst (IHC). Anterior interhemispheric ssure is complete between the frontal lobes (white arrow) and contains an azygous anterior cerebral artery. Sagittal T2weighted image (C) shows lack of a visible cerebral aqueduct. On axial image of the midbrain (not shown), the aqueduct was not visible and the tectum appeared dysplastic with nonseparation of the colliculi.

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Figure 13. A,B: fetal MRI of a 26-week gestational age (GA) fetus with trisomy 13 and semilobar HPE. HASTE fetal sequences in midsagittal plane (A) show and moderate size dorsal cyst and inferior cerebellar vermis hypoplasia (Dandy Walker complex). The thalami and basal ganglia appear fused on axial image (B). C, D: fetal MRI of a 33-week gestational age fetus with alobar HPE. Single-shot fast spin echo MR sequences in sagittal (C) and axial (D) planes show poorly separated frontal lobes and a large monoventricle that communicates with a large dorsal cyst. The gyral pattern is more complex than that of the 26-week GA fetus.

absent septum pellucidum, and hydrocephalus with communication of the lateral ventricles, are sometimes misdiagnosed prenatally as HPE [Malinger et al., 2005]. The detection of craniofacial malformations associated with HPE on prenatal imaging often aid in the diagnosis of HPE. See Mercier et al. [2010] for information on molecular prenatal diagnosis.

Foundation, and the Crowley-Carter Foundation. We thank Nancy Clegg and Elaine Stashinko from the Carter Centers for providing the source images.

REFERENCES
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ACKNOWLEDGMENTS
This research was supported by the Carter Centers for Brain Research in Holoprosencephaly and Related Malformations, the Don and Linda Carter

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