Upload
familiesforhope
View
87
Download
3
Tags:
Embed Size (px)
DESCRIPTION
Holoprosencephaly(HPE)isacomplexcongenitalbrainmalformationcharacterizedbyfailureoftheforebraintobifurcate into two hemispheres, a process normally completed by the fifth week of gestation. Modern high-resolution brain magnetic resonance imaging (MRI) has allowed detailed analysis of the cortical, white matter, and deep gray structural anomalies in HPE in living humans.
Citation preview
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:Refining the Spectrum of the Midline MalformationJIN S. HAHN* AND PATRICK D. BARNES
Holoprosencephaly (HPE) is a complex congenital brain malformation characterized by failure of the forebrain tobifurcate into two hemispheres, a process normally completed by the fifth week of gestation. Modern high-resolution brain magnetic resonance imaging (MRI) has allowed detailed analysis of the cortical, white matter, anddeep gray structural anomalies in HPE in living humans. This has led to better classification of types of HPE,identification of newer subtypes, and understanding of the pathogenesis. Currently, there are four generallyaccepted subtypes of HPE: alobar, semilobar, lobar, and middle interhemispheric variant. These subtypes aredefined primarily by the degree and region of neocortical nonseparation. Rather than there being four discretesubtypes of HPE, we believe that there is a continuum of midline neocortical nonseparation resulting in a spectrumdisorder. Many patients with HPE fall within the border zone between the neighboring subtypes. In addition, thereare patients with very mild HPE, where the nonseparation is restricted to the preoptic (suprachiasmic) area. Inaddition to the neocortex, other midline structures such as the thalami, hypothalamic nuclei, and basal ganglia areoften nonseparated in HPE. The cortical and subcortical involvements in HPE are thought to occur due to adisruption in the ventral patterning process during development. The severity of the abnormalities in thesestructures determines the severity of the neurodevelopmental outcome and associated sequelae.� 2010 Wiley-Liss, Inc.
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: Refiningthe spectrum of the midline malformation. Am J Med Genet Part C Semin Med Genet 154C:120–132.
INTRODUCTION
Holoprosencephaly (HPE) is a complex
congenital brain malformation charac-
terized by failure of the forebrain to
bifurcate into two hemispheres, a proc-
ess normally complete by the fifth week
of gestation [Golden, 1999]. Modern
high-resolution brain magnetic reso-
nance imaging (MRI) has allowed
detailed analysis of the cortical, white
matter, and deep gray structural anoma-
lies in HPE. This has led to better
classification of types of HPE, identi-
fication of newer subtypes, and under-
standing of the pathogenesis.
DEFINITION ANDCLASSIFICATION
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 telence-
phalon and diencephalon. Sometimes
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
Jin Hahn, M.D. Professor of Neurology and Pediatrics, Stanford University School of Medicineand Lucile Packard Children’s Hospital. Medical Director, Stanford Carter Center for Research inHoloprosencephaly and Related Brain Malformations. Research interests: brain development andmalformations, 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 Children’sHospital at Stanford Research interests: Advanced imaging, including magnetic resonanceimaging, of injury to the developing central nervous system; including fetal, neonatal, infant andyoung child; and, including nonaccidental injury (e.g., child abuse).
Grant sponsor: Carter Centers for Brain Research in Holoprosencephaly and RelatedMalformations; Grant sponsor: Don and Linda Carter Foundation; Grant sponsor: Crowley-Carter Foundation.
*Correspondence to: Jin S. Hahn, Department of Neurology, Stanford University MedicalCenter, 300 Pasteur Drive, Room A343, Stanford, CA 94305-5235, USA.E-mail: [email protected]
DOI 10.1002/ajmg.c.30238Published online 26 January 2010 in Wiley InterScience (www.interscience.wiley.com)
� 2010 Wiley-Liss, Inc.
structure actively merging. HPE has
traditionally been classified according
to the DeMyer’s 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 syn-
telencephaly has been characterized
[Lewis et al., 2002; Simon et al., 2002].
The neuroimaging findings of these
types are provided below and summar-
ized 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 mid-
line 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 monoventr-
icle. 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 fissures
are splayed open [Takahashi et al., 2004].
The interhemispheric fissure, falx cere-
bri, and corpus callosum are completely
absent. The basal ganglia and hypothala-
mic and thalamic nuclei often lack sepa-
ration resulting in absence of the third
ventricle [Simon and Barkovich, 2001].
At times, a mass of deep gray matter is
present with poorly differentiated stria-
tum and thalamus (Fig. 1B) and may in-
clude parts of the mesencephalon. This
mass may be attached to the holosphere
by a small anterior midline hinge of
tissue that lacks corticospinal, cortico-
thalamic, 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 Semilobar Lobar MIH
Cortical
nonseparation
Diffuse (holosphere) Frontal Basal frontal Posterior frontal and
parietal
Corpus callosum Absent Rostrum, genu, and
body absent. Splenium
present
Rostrum and genu
absent. Anterior body
variably present.
Splenium present
Body absent; genu
variably present.
Splenium present
IHF and Falx Completely absent
anteriorly and
posteriorly
Present posteriorly only Hypoplastic anteriorly
and present posteriorly
Absent in the posterior
frontal and parietal
region
Ventricles Monoventricle
communicating
widely with dorsal cyst
Anterior horns absent.
Posterior horns
present. Small third
ventricle
Rudimentary anterior
horns. Third ventricle
formed
Normal or hypoplastic
anterior horns. Third
ventricle formed
Dorsal cyst Usually present Variably present Absent Present in 1/4
Septum pellucidum Absent Absent Absent or dysplastic Absent
Thalamus Often fused Partial fusion Usually fully separated Fused in 1/3 to 1/2
Basal ganglia Often fused (may form
single mass with
thalami)
Partial fusion (especially
head of caudate)
Variable degree of fusion Separated
Hypothalamus Always fused to some
degree (100%)
Very often fused to some
degree (98%)
Often fused to some
degree (83%)
Separated
Sylvian fissure Often absent Anteriorly and medially
displaced (wide sylvian
fissure) with fused
frontal lobe
Anteriorly and medially
displaced (wide sylvian
fissure) with small
frontal lobes
Often abnormally
connected across the
midline over the
vertex
Cortical dysplasia
and heterotopic gray
matter
Frequent presence of
diffuse broad gyri with
too few sulci
Occasional broad gyri
with too few sulci
Rare midline subcortical
heterotopias in frontal
regions
Very common
Cerebral vasculature Rete of vessels branching
from the internal
cerebral arteries
Azygous anterior
cerebral artery
Azygous anterior
cerebral artery
Azygous anterior
cerebral artery
Based on Simon et al. [2000, 2002], Plawner et al. [2002].
ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 121
Affected children with alobar HPE
are typically abnormal from the neonatal
period and present with hypotonia and
seizures. Midline craniofacial mal-
formations including hypotelorism, pre-
maxillary hypogenesis and cleft, and
hypoplastic nose are often present. A
large dorsal cyst may result in hydro-
cephalus and macrocephaly. Otherwise,
the head is microcephalic.
Semilobar HPE
In semilobar HPE, the anterior hemi-
spheres fail to separate, while some
portions of the posterior hemispheres
show separation (Fig. 3). The non-
cleaved frontal lobes are usually small.
Figure 1. MRI of a 1-day-old neonate with alobar HPE. Sagittal T1-weighted image (A) shows absence of corpus callosum and amonoventricle (MV) that communicates with the dorsal cyst. Axial T1-weighted image at the level of the thalami (B) demonstrates largecentral gray mass that consists of thalamic nuclei and basal ganglia (arrowheads). At a more rostral level axial T1-weighted image (C) shows acrescentic shaped MV surrounded by a flattened holosphere and large dorsal cyst (DC) posteriorly.
Figure 2. MRI of a 5-day-old newborn with alobar HPE. Sagittal T1-weight image (A) shows a holosphere that takes up more thanhalf of the cranial vault. Corpus callosum is not visualized. The ventricular system is composed of a single midline monoventricle (MV) thatcommunicates openly with the posteriorly positioned dorsal cyst (DC). Axial T2-weighted image (B) shows lack of separation of thehemispheres. The holosphere extends further posteriorly (compared to the patient in Fig. 1) forming a cup-like holosphere. The caudateand lentiform nuclei are not well differentiated and are fused in the midline (white arrow). Coronal T2-weighted image (C) shows acontinuity of gray matter in the midline without an interhemispheric fissure. The thalamic nuclei are partially fused (black arrow).
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.
122 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE
The frontal horns of the lateral ventricle
are absent, but posterior horns and
trigones are present. The septum pellu-
cidum is absent. The corpus callosum is
absent anteriorly, but the splenium of the
corpus callosum is present. The anterior
extent of the corpus callosum develop-
ment also correspond with the anterior
extent of the interhemispheric fissure
formation [Simon and Barkovich,
2001]. On imaging studies, some por-
tions of the posterior interhemispheric
fissure, falx cerebri, and splenium of the
corpus callosum can be identified. The
hippocampal formation in the temporal
lobes appears normal and the temporal
limbs of the choroid fissures are closed
[Takahashi et al., 2004]. The deep gray
nuclei are incompletely separated and
can usually be identified 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 some-
times 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 micro-
cephalic, 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.
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 fissure
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 hypo-
plastic. An azygous anterior cerebral
artery (ACA) is usually present in the
anterior IHF.
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 fissures in most patients are
oriented nearly vertically and were
abnormally connected across the mid-
line over the vertex of the brain [Simon
et al., 2002]. Approximately two-thirds
of the MIH patients have either sub-
cortical heterotopic gray matter or
cortical dysplasia. Abnormally thick
cortex lining the anterior interhemi-
spheric fissure was often present and was
contiguous across the midline. As in
other types of HPE, the anterior vascu-
Figure 3. MRI of a 7-month-old infant girl with semilobar HPE. Sagittal T1-weighted image (A) demonstrates absence of the genuand body of the corpus callosum, but presence of the splenium (white arrowheads). Axial T2-weighted image (B) shows absence ofinterhemispheric fissure anteriorly. The posterior hemispheres are well separated and the posterior horns of the lateral ventricles are wellformed. The head of the caudate are nonseparated and the thalami are partially separated. The third ventricle is abnormal and the frontalhorns are absent. Coronal T2-weighted image (C) at the level of the thalami shows a shallow interhemispheric fissure (black arrowheads) andfusion of cortical matter at the midline.
ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 123
lature is abnormal with an azygous ACA
noted in all patients. Patients usually
have normal or large intraocular dis-
tances (hypertelorism).
Septo-Optic Dysplasia and HPE
Some of the patients with lobar HPE
may fall within the spectrum of septo-
optic 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–pitui-
tary axis abnormality resulting in endo-
crinopathies. Careful examination of the
MRI images will show anterior callosal
dysgenesis and hypothalamic or pre-
optic area dysgenesis or fusion (Fig. 6).
Figure 4. MRI of a 19-month-old boy with lobar HPE. Sagittal T1-weighted image (A) demonstrates the presence of posterior bodyand splenium of the corpus callosum (arrowheads), but the genu is not developed and the anterior body is very hypoplastic. Axial T2-weighted image (B) shows that the anterior and posterior interhemispheric fissures (IHFs) are present (arrows). The cerebral hemispheresthat 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 flow void is present in the anterior IHF. The fontal horns are rudimentary. CoronalSPGR image (C) shows failure of complete separations of the frontal lobes across the interhemispheric fissure (curved arrow) and continuousgray matter in the basal frontal regions (arrow).
Figure 5. MRI of a child with an initial diagnosis of septo-optic dysplasia and diabetes insipidus taken at 1 month of age. Sagittal T1-weight image (A) shows absence of rostrum and genu of the corpus callosum (arrowheads). Axial T2-weighted image (B) shows absence ofthe septum pellucidum and hypoplastic frontal horns. Coronal T1-weighted image (C) shows absence of the septum pellucidum and theanterior corpus callosum. The hypothalamus and basal structures appear to be fused and the third ventricle is not well formed. The opticchiasm was noted to be hypoplastic and was given diagnosis of septo-optic dysplasia. She had optic nerve hypoplasia, visual impairment,multiple endocrine deficiencies, and diabetes insipidus. At 2.5 years of age lobar HPE was diagnoses based on this MRI.
124 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE
Without evidence of nonseparation in
these regions, the patient should be
classified as having septo-optic dysplasia
only, not HPE.
Spectrum of Hemispheric
Nonseparation in HPE
The classification of classic HPE based
on the degree of hemispheric non-
separation falls within a spectrum.
DeMyer [1987] brought attention to
this spectrum when he stated, ‘‘from the
holospheric brain with no hint of an
interhemispheric fissure, the spectrum
of the malformation extends in unbro-
ken 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 abnormal-
ities in the degree of hemispheric
nonseparation.
Continuum between semilobar and
lobar HPE
For example, the precise distinction
between lobar and semilobar HPE is
difficult in some patients, as there is a
continuum of nonseparation of the
frontal lobes and development of the
anterior interhemispheric fissure and
anterior falx. Generally, the patient is
classified 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 difficult 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 classification 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 dys-
genesis may involve all of these callosal
areas (excluding the splenium).
Minimal Forms of HPE
We have identified several patients
with a minimal form of HPE with
abnormal midline fusion limited to the
preoptic area (involving the suprachias-
mic region and anterior hypothalamus)
or the septal region (subcallosal region)
(Fig. 8). These patients have no
or minimal fusion of the frontal neo-
cortex. The fornices are often thickened
and dysplastic and the anterior commis-
sure may also be maldeveloped. An
azygous ACA is often present. These
patients are often brought to imaging
because of subtle craniofacial malforma-
tion such as single median maxillary
central incisor (SMMCI) and congeni-
tal 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 commis-
sure to essentially exclude the diagnosis
of HPE, especially when the two
cerebral hemispheres are completely
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). Thebody of the corpus callosum is absent in the region of nonseparated hemispheres (whitecurved arrow). Coronal inversion-recovery image (B) at level of lentiform nucleidemonstrate continuity of the gray matter (black arrowheads) and absent septumpellucidum. 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 corpuscallosum and absent septum pellucidum. At a higher level, axial FLAIR image (D) showsanteriorly displaced sylvian fissures with abnormal gray matter crossing the midline.
ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 125
separated (i.e., absence of neocortical
fusion). Nevertheless, both the preoptic
area and the septal region are tele-
ncephalic 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
definition exclude brain involvement.
OTHER BRAINSTRUCTURES INVOLVEDIN HPE
In addition to the hemispheric non-
separation, 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 findings and clinical character-
istics [Lewis et al., 2002; Plawner et al.,
2002] and led to a better understanding
of the embryological derangements that
lead to HPE.
Figure 7. MRI of 20-month-old girl with features of lobar HPE and MIH. Axial T2-weighted image (A) shows smallunderdeveloped frontal horns and absence of septum pellucidum. Gray matter band and azygous anterior cerebral artery are noted in midlinein the shallow anterior interhemispheric fissure. 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).
Figure 8. MRI of a 10-year-old boy with learning disabilities, single median maxillary central incisor, congenital nasal pyriform aperturestenosis, and endocrinopathies. T1-weighted midsagittal image (A) shows hypoplasia of the rostrum of corpus callosum and a rectangular areaof abnormality in the subcallosal region, anterior to the hypothalamic region (white arrowheads). The dysplastic appearing fornix is anterior tothis region (white arrows). T2-weighted axial image (B) shows well-developed anterior and posterior interhemispheric fissures and an azygousanterior cerebral artery flow void in the interhemispheric fissure. 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). CoronalSPGR image (C) slight anterior to the anterior commissure shows the dysplastic fornix (white arrows) traveling below the septum pellucidumand inferior to that the area of midline fusion (white arrowheads).
126 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE
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 high-
quality 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 hypo-
thalamic 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.
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.
In 27% of the patients, the mesen-
cephalon showed some degree of non-
separation, implying that in a large
proportion of patients the rhombence-
phalon is also disturbed during develop-
ment. 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, sup-
ports the theory that a lack of induction
of the most rostral aspects of the
embryonic floor plate is the cause of
classic HPE. The finding of mesence-
phalic abnormalities implies that in the
abnormal development in HPE, the
rostral-caudal gradient at times extends
more caudally beyond the prosencepha-
lon.
Midline Dorsal Cyst
Dorsal cysts are more often present in
alobar HPE (92%), compared to semi-
lobar HPE (28%) and lobar HPE (9%)
[Plawner et al., 2002] (Figs. 1 and 2). The
presence of dorsal cysts strongly corre-
lates 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 expan-
sion of the posterodorsal portion of the
ventricle to form the dorsal cyst. Sup-
porting this theory, hydrocephalus is
often, but not always, noted in associa-
tion with dorsal cysts [Simon and
Barkovich, 2001; Plawner et al., 2002].
Two-fifth of HPE patients with dorsal
cyst require CSF shunting procedure
[Plawner et al., 2002]. Additional abnor-
malities of the cerebral aqueduct of
Sylvius, such as atresia or stenosis that
have been found in HPE on neuro-
pathologic examination [Vogel et al.,
1990] may also contribute to the
obstruction of CSF flow and require-
ment for shunting.
The gross morphologic descrip-
tions of the holosphere as pancake, cup,
or ball shape is a reflection of the size of
the dorsal cyst. Smaller dorsal cysts may
remain stable without causing hydro-
cephalus, or disappear after a CSF
shunting procedure. Occasionally, the
dorsal cyst herniates through the ante-
rior fontanelle to form a vertex ence-
phalocele that is unique in HPE [Sarnat
and Flores-Sarnat, 2001].
The dorsal cyst of HPE is similar in
appearance to the interhemispheric cyst
Figure 9. Hypothalamic involvement in HPE. Coronal T2-weighted image (A) in16-year-old girl with lobar HPE demonstrates complete separate of the hypothalamuswith fully formed third ventricle. Coronal T2-weighted FSE image (B) in a neonate withsemilobar HPE reveals complete nonseparation of the hypothalamus and absent thirdventricle.
ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 127
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. Differentiat-
ing these can be especially difficult when
the abnormal brain anatomy is further
distorted by hydrocephalus. Definitive
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 thick-
ness was normal in all patients, and
gyral/sulcal sizes were normal in 83%
[Barkovich et al., 2002a]. Diffuse dys-
plastic 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 localization-
related epilepsy.
In the most severe patient with
alobar HPE, no sylvian fissure can be
identified. In less severe forms the
sylvian fissures are displaced more ante-
riorly and medially as HPE reflecting the
degree of frontal lobe development
[Barkovich et al., 2002a]. The degree
of the displacement of the sylvian fissures
(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 abnormal-
ities [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, confirming
the findings from prior neuropatholog-
ical studies [Kobori et al., 1987]. In most
patients with less severe types of HPE,
the corticospinal tracts were present
bilaterally. HPE type and neurodevelop-
mental score correlated strongly with
cortico-ponto-spinal tracts and middle
cerebellar peduncle dimensions. Thick-
ened dysplastic fornices have been noted
with DTI tractography in a patient with
semilobar HPE [Rollins, 2005]. These
findings 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 pos-
terior fossa abnormalities such as rhom-
bencephalosynapsis, in which there is
abnormal nonseparation of the cerebel-
lar 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) andcoronal (B) T2-weighted images shows very simplified gyral pattern with broad gyri andtoo few sulci. The images also show fusion of the thalamic nuclei and large monoventriclewithout a clear dorsal cyst.
128 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE
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.
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.
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 inter-
hemispheric fissures 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 ventric-
ular system and dorsal cyst, cortical
malformations, subcortical heterotopia,
sylvian fissure development, optic
nerves and chiasm, and olfactory bulbs
and tracts. The posterior fossa should
also be examined carefully for abnor-
malities, including aqueductal dysgene-
sis, Dandy–Walker complex, Chiari
malformations, cerebellar abnormalities,
and other brainstem abnormalities.
Extracerebral structures that alsowarrant
review are the presence of an SMMCI,
CNPAS, premaxillary clefts, other mid-
line clefts, and distance between the eyes
(for hypo- or hypertelorism). When
these extracerebral anomalies are found,
careful attention should be paid atten-
tion 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. Difficul-
ties in assessment also occur when
hydrocephalus distorts underlying brain
structures [Simon and Barkovich, 2001].
Definitive diagnosis in these patients
may require repeat MRI after ventricu-
loperitoneal shunting.
Ideally, a pediatric neuroradiologist
with experience in brain malformations
should review the imaging studies.
Approximately 1/5 to 1/3 of the imag-
ing 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 septo-
optic dysplasia, absent septum pelludi-
cum with schizencephaly, agenesis of
corpus callosum, or callosal agenesis
with interhemispheric cyst (CAIHC).
Figure 11. A,B: MRI of a 2-year-old girl with lobar holoprosencephaly andsubcortical heterotopia. Axial T2-weighted (A) and oblique coronal STIR (B) imagesshow large subcortical gray matter heterotopia (white arrowheads) located in the rightfrontal lobe white matter in addition to midline gray matter fusion in the anteriorinterhemispheric fissure. This patient also had refractory epilepsy. C: T2-weightedcoronal MRI of a 1.5-year-old patient with MIH and subcortical heterotopia consistingof large infolding dysplastic cortex (black arrowheads). This child also had severelocalization-related epilepsy. D: Coronal spoiled gradient-recalled image in a patientwith semilobar HPE shows heterotopia gray at the roof of the monoventricle (whitearrowheads).
ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 129
CAIHC type 1b is frequently mis-
diagnosed 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 in-
terhemispheric 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 creat-
ing a blockage of CSF egress. Some
authors refer to this malformation as
‘‘holodiencephaly,’’ meaning that the
diencephalon, but not the telencepha-
lon, 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 thala-
mic fusion may share similar pathoge-
netic mechanisms involved in HPE, and
further studies are needed to understand
the boundaries and continuities of mid-
line malformations.
Three-dimensional MRI with
reconstruction may provide comple-
mentary anatomic information that is
not apparent from conventional MRI
[Takahashi et al., 2003; Takahashi et al.,
2004]. In semilobar HPE three-dimen-
sional reconstructions reveal a rostro-
caudally aligned midline gray matter
‘‘seam’’ that extends from the supra-
chiasmatic hypothalamus to a caudally
positioned diminutive body and sple-
nium of the corpus callosum [Takahashi
et al., 2003]. In the rostral to caudal
direction, the interhemispheric fissure
also transitions from being absent, to a
shallow but deepening zone, and finally
to a zone where the fissure 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 first
trimester [Filly et al., 1984; Nyberg
et al., 1987; Tongsong et al., 1999].
Failure to identify the characteristics of
the developing choroid plexuses (‘‘but-
terfly sign’’) during the first 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 ultrasonogra-
phy for detection of milder forms of
HPE (lobar and MIH) may be low, since
in these forms the anterior and posterior
interhemispheric fissures are present and
the characteristic dorsal cyst of HPE is
often absent. In our experience, prenatal
ultrasonography had low sensitivity.
Although prenatal ultrasound was per-
formed 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 significantly 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-weightedaxial (A) and coronal (B) images show thalamic fusion (black arrows) and a very large interhemispheric cyst (IHC). Anteriorinterhemispheric fissure is complete between the frontal lobes (white arrow) and contains an azygous anterior cerebral artery. Sagittal T2-weighted image (C) shows lack of a visible cerebral aqueduct. On axial image of the midbrain (not shown), the aqueduct was not visible andthe tectum appeared dysplastic with nonseparation of the colliculi.
130 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE
absent septum pellucidum, and hydro-
cephalus with communication of the
lateral ventricles, are sometimes mis-
diagnosed prenatally as HPE [Malinger
et al., 2005]. The detection of craniofa-
cial 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.
ACKNOWLEDGMENTS
This research was supported by the
Carter Centers for Brain Research
in Holoprosencephaly and Related Mal-
formations, the Don and Linda Carter
Foundation, and the Crowley-Carter
Foundation. We thank Nancy Clegg
and Elaine Stashinko from the Carter
Centers for providing the source images.
REFERENCES
Albayram S, Melhem ER, Mori S, Zinreich SJ,Barkovich AJ, Kinsman SL. 2002. Holopro-sencephaly in children: Diffusion tensorMR imaging of white matter tracts of thebrainstem-initial experience. Radiology223:645–651.
Barkovich AJ, Fram EK, Norman D. 1989. Septo-optic dysplasia: MR imaging. Radiology171:189–192.
Barkovich AJ, Simon EM, Walsh CA. 2001.Callosal agenesis with cyst: A better under-standing and new classification. Neurology56:220–227.
Barkovich AJ, Simon EM, Clegg NJ, Kinsman SL,Hahn JS. 2002a. Analysis of the cerebralcortex in holoprosencephaly with attentionto the sylvian fissures. AJNR Am J Neuro-radiol 23:143–150.
Barkovich AJ, Simon EM, Glenn OA, Clegg NJ,Kinsman SL, Delgado M, Hahn JS. 2002b.MRI shows abnormal white matter matura-tion in classical holoprosencephaly. Neurol-ogy 59:1968–1971.
DeMyer W. 1987. Holoprosencephaly (cyclopia-arhinencephaly). In: Vinken PJ, Bruyn GW,Klawans HL, editors. Handbook of clinicalneurology. Revised series, 6th edition.Amsterdam: Elsevier Science Publishers.pp 225–244.
Filly RA, Chinn DH, Callen PW. 1984. Alobarholoprosencephaly: Ultrasonographic pre-natal diagnosis. Radiology 151:455–459.
Golden JA. 1999. Towards a greater understand-ing of the pathogenesis of holoprosence-phaly. Brain Dev 21:513–521.
Hahn J, Clegg N, Delgado M, Stashinko E, BarnesP. 2008. Holoprosencephaly: An oftenmisdiagnosed disorder. Ann Neurol 64:S97.
Kobori JA, Herrick MK, Urich H. 1987.Arhinencephaly. The spectrum of associatedmalformations. Brain 110:237–260.
Lewis AJ, Simon EM, Barkovich AJ, Clegg NJ,Delgado MR, Levey E, Hahn JS.2002. Middle interhemispheric variant ofholoprosencephaly: A distinct cliniconeuror-adiologic subtype. Neurology 59:1860–1865.
Malinger G, Lev D, Kidron D, Heredia F,Hershkovitz R, Lerman-Sagie T. 2005.Differential diagnosis in fetuses with absentseptum pellucidum. Ultrasound ObstetGynecol 25:42–49.
Marcorelles P, Laquerriere A. 2010. Neuropathol-ogy of holoprosencephaly. Am J MedGenet Part C Semin Med Genet 154C:109–119.
Mercier S, Dubourg C, Belleguic M, Pasquier L,Loget P, Lucas J, Bendavid C, Odent S.2010. Genetic counseling and ‘‘molecular’’prenatal diagnosis of holoprosencephaly(HPE). Am J Med Genet Part C SeminMed Genet 154C:191–196.
Muenke M. 1995. Holoprosencephaly: Defectsof the mediobasal prosencephalon. In:Norman MG, McGillivray BC, KalousekDK, Hill A, Poskitt KJ, editors. Congenitalmalformations of the brain: Pathological,embryological, clinical, radiological andgenetic aspects. New York: Oxford Uni-versity Press. pp 187–221.
Nyberg DA, Mack LA, Bronstein A, Hirsch J,Pagon RA. 1987. Holoprosencephaly: Pre-natal sonographic diagnosis. AJR Am JRoentgenol 149:1051–1058.
Peebles DM. 1998. Holoprosencephaly. PrenatDiagn 18:477–480.
Picone O, Hirt R, Suarez B, Coulomb A,Tachdjian G, Frydman R, Senat MV. 2006.Prenatal diagnosis of a possible new middleinterhemispheric variant of holoprosence-phaly using sonographic and magneticresonance imaging. Ultrasound ObstetGynecol 28:229–231.
Plawner LL, Delgado MR, Miller VS, Levey EB,Kinsman SL, Barkovich AJ, Simon EM,Clegg NJ, Sweet VT, Stashinko EE, Hahn
Figure 13. A,B: fetal MRI of a 26-week gestational age (GA) fetus with trisomy 13and semilobar HPE. HASTE fetal sequences in midsagittal plane (A) show and moderatesize dorsal cyst and inferior cerebellar vermis hypoplasia (Dandy–Walker complex). Thethalami and basal ganglia appear fused on axial image (B). C, D: fetal MRI of a 33-weekgestational 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 monoventriclethat communicates with a large dorsal cyst. The gyral pattern is more complex than that ofthe 26-week GA fetus.
ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 131
JS. 2002. Neuroanatomy of holoprosence-phaly as predictor of function: Beyond theface predicting the brain. Neurology 59:1058–1066.
Pulitzer SB, Simon EM, Crombleholme TM,Golden JA. 2004. Prenatal MR findings ofthe middle interhemispheric variant ofholoprosencephaly. AJNR Am J Neuro-radiol 25:1034–1036.
Rollins N. 2005. Semilobar holoprosencephalyseen with diffusion tensor imaging and fibertracking. AJNR Am J Neuroradiol 26:2148–2152.
Sarnat HB, Flores-Sarnat L. 2001. Neuropatho-logic research strategies in holoprosence-phaly. J Child Neurol 16:918–931.
Sepulveda W, Dezerega V, Be C. 2004. First-trimester sonographic diagnosis of holopro-sencephaly: Value of the ‘‘butterfly’’ sign. JUltrasound Med 23:761–765, quiz 766–767.
Simon EM, Barkovich AJ. 2001. Holoprosence-phaly: New concepts. Magn Reson ImagingClin N Am 9:149–164.
Simon EM, Hevner R, Pinter JD, Clegg NJ,Miller VS, Kinsman SL, Hahn JS, BarkovichAJ. 2000. Assessment of the deep gray nucleiin holoprosencephaly. AJNR Am J Neuro-radiol 21:1955–1961.
Simon EM, Hevner RF, Pinter JD, CleggNJ, Delgado M, Kinsman SL, Hahn JS,Barkovich AJ. 2001. The dorsal cyst in
holoprosencephaly and the role of thethalamus in its formation. Neuroradiology43:787–791.
Simon EM, Hevner RF, Pinter JD, Clegg NJ,Delgado M, Kinsman SL, Hahn JS, Barko-vich AJ. 2002. The middle interhemisphericvariant of holoprosencephaly. AJNR Am JNeuroradiol 23:151–155.
Sonigo PC, Rypens FF, Carteret M, DelezoideAL, Brunelle FO. 1998. MR imaging offetal cerebral anomalies. Pediatr Radiol 28:212–222.
Stashinko EE, Clegg NJ, Kammann HA, SweetVT, Delgado MR, Hahn JS, Levey EB.2004. A retrospective survey of perinatal riskfactors of 104 living children with holopro-sencephaly. Am J Med Genet 128A:114–119.
Takahashi T, Kinsman S, Makris N, Grant E,Haselgrove C, McInerney S, KennedyDN, Takahashi T, Fredrickson K, Mori S,Caviness VS. 2003. Semilobar holoprosen-cephaly with midline ‘seam’: A topologicand morphogenetic model based upon MRIanalysis. Cereb Cortex 13:1299–1312.
Takahashi TS, Kinsman S, Makris N, Grant E,Haselgrove C, McInerney S, Kennedy DN,Takahashi TA, Fredrickson K, Mori S,Caviness VS. 2004. Holoprosencephaly-topologic variations in a liveborn series: Ageneral model based upon MRI analysis. JNeurocytol 33:23–35.
Takanashi J, Barkovich AJ, Clegg NJ, DelgadoMR. 2003. Middle interhemispheric variantof holoprosencephaly associated with diffusepolymicrogyria. AJNR Am J Neuroradiol24:394–397.
Tongsong T, Wanapirak C, Chanprapaph P,Siriangkul S. 1999. First trimester sono-graphic diagnosis of holoprosencephaly. Int JGynaecol Obstet 66:165–169.
Vogel H, Gessaga EC, Horoupian DS, Urich H.1990. Aqueductal atresia as a feature ofarhinencephalic syndromes. Clin Neuro-pathol 9:191–195.
Widjaja E, Massimi L, Blaser S, Di Rocco C,Raybaud C. 2007. Midline ‘‘brain in brain’’:An unusual variant of holoprosencephalywith anterior prosomeric cortical dysplasia.Childs Nerv Syst 23:437–442.
Wong AM, Bilaniuk LT, Ng KK, Chang YL,Chao AS, Wai YY. 2005. Lobar holopro-sencephaly: Prenatal MR diagnosis withpostnatal MR correlation. Prenat Diagn25:296–299.
Yamada S, Uwabe C, Fujii S, Shiota K. 2004.Phenotypic variability in human embryonicholoprosencephaly in the Kyoto Collection.Birth Defects Res A Clin Mol Teratol 70:495–508.
Young JN, Oakes WJ, Hatten HPJr. 1992. Dorsalthird ventricular cyst: An entity distinct fromholoprosencephaly. J Neurosurg 77:556–561.
132 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE