PRENATAL DIAGNOSIS

Prenat Diagn 2009; 29: 340–354.

Published online 30 January 2009 in Wiley InterScience
(www.interscience.wiley.com) DOI: 10.1002/pd.2208

REVIEW

Disorders of prosencephalic development

P. Volpe*, G. Campobasso, V. De Robertis and G. Rembouskos
Fetal Medicine Unit, Di Venere and Sarcone Hospitals, Bari, Italy

Abnormal ventral induction may result in disorders of formation, cleavage, and midline development of prosen-
cephalic structures. Holoprosencephaly is a developmental field defect of impaired cleavage of prosencephalon.
The most widely accepted classification of holoprosencephaly recognizes three major varieties: the alobar,
semilobar and lobar types, according to the severity of the malformation. The brain malformations, character-
ized by the fusion of the cerebral hemisphere along the midline are commonly associated with facial anomalies.
Corpus callosum agenesis and septo-optic dysplasia are disorders of prosencephalic midline development,
and usually have less severe presentations but still, affected subjects may suffer from neurodevelopmental
retardation, and/or endocrinologic and visual disorders.
In this article we report an up-to-date of pathogenesis, prenatal sonographic findings, differential diagnosis
and prognosis of the aforementioned anomalies. Copyright  2009 John Wiley & Sons, Ltd.
KEY WORDS: septum pellucidum; holoprosencephaly; corpus callosum; fetal neurosonography; CNS anomalies;
fetal ultrasound < fetal imaging

INTRODUCTION major telencephalic commissure. The telencephalic (or

After the end of primary neurulation, the cephalic part
of the neural tube gives rise to three primary vescicles:
the hindbrain (rhombencephalon), the mid-brain (mesen-
cephalon) and the forebrain structures (prosencephalon).
The process of ventral induction, leading to the develop-
ment of the prosencephalon consists of three sequential
events that are closely interconnected: formation, cleav-
age and midline development (Volpe, 2000).
Disorders of prosencephalic formation are represented
by aprosencephaly and atelencephaly and are extremely
rare.
Holoprosencephaly (HPE) is a well-known disorder of
prosencephalic cleavage. In the past, HPE was confused
with ‘arhinencephaly’, thereby stressing the absence of
olfactory structures. Subsequently De Myer and Zeman
(DeMyer and Zeman, 1963) introduced the term HPE,
which identifies more clearly the lack of cleavage and
differentiation of the prosencephalon as the main causal
factor.
Disorders of prosencephalic midline development are
mainly represented by agenesis of corpus callosum
(ACC), agenesis of septum pellucidum (ASP) and septo-
optic dysplasia (SOD).
Since ventral induction is closely related to facial
development, many fetuses with prosencephalic disor-
ders are also affected by various facial anomalies.
Disorders of prosencephalic midline
development
Agenesis of the corpus callosum
Anatomy and morphogenesis of the corpus
callosum: The corpus callosum (CC) represents the
*Correspondence to: P. Volpe, Fetal Medicine Unit, Di Venere
and Sarcone Hospitals, Bari, Italy. E-mail: paolo-volpe@libero.it
interhemispheric) commissures are cortico-cortical bun-
dles of white matter extending from one hemisphere to
the other, typically but not absolutely in a symmetrical
fashion (Barkovich, 2000; Raybaud and Girard, 2005).
The other interhemispheric commissures are the anterior
and the hippocampal commissures.
Surrounded by these commissures, the septum pel-
lucidum (SP) also carries commissural fibers (Shu and
Richards, 2001). In the fetus, the leaves of the SP enclose
the space of the cavum septi pellucidi (CSP), which is
located under the anterior portion of the CC.
The commissures are formed from two distinct sites
(Rakic and Yakovlev, 1968), the lamina reuniens (within
the lamina terminalis) for the anterior commissure and
the massa commissuralis (by fusion of the medial walls
of the hemispheres) for both the hyppocampal commis-
sure and the CC. A well-defined callosal plate is obvious
by weeks 12–14 and the CC is virtually complete by
week 20 (Barkovich, 2000; Raybaud and Girard, 2005).
Anomalies of the commissures may include agenesis
of all structures or may only be missing individually. In
most of the cases, agenesis of the CC is only a part of
the disorder: typically, the hyppocampal commissure is
also missing or is incomplete.
The CC is composed of four parts (from front to back):
rostrum, genu, body and splenium (Figures 1, 2). The
formation of the CC starts with the development of the
genu; the body and splenium develop at a later stage. If
the normal developmental process is disturbed, the CC
may be completely or partially absent (PACC) (hypoge-
netic) (Barkovich, 2000, 2002; Volpe et al., 2006; Ray-
baud and Girard, 2005). As the developmental process
starts from the anterior part and progresses front to rear,
when the CC is hypogenetic it is usually the posterior
portion that gets affected (the posterior body and the
splenium). There has been some debate about the tim-
ing of the development of the rostrum, the small frontal

Copyright  2009 John Wiley & Sons, Ltd. Received: 6 September 2008
Revised: 2 December 2008
Accepted: 5 December 2008
Published online: 30 January 2009
 DISORDERS OF PROSENCEPHALIC DEVELOPMENT 341

part of the CC. Whereas clinical observation appears to

agree that this should be the last portion to develop,
recent studies based on diffusion tensor magnetic reso-
nance imaging were able to demonstrate that the rostrum
together with the genu and the anterior part of the body
were already present at around 15 weeks (Ren et al.,
2006).
The knowledge of the organogenetic process helps
to differentiate a developmental damage (hypogene-
sia) from an acquired one (destruction). The latter
mechanism usually occurs in association with hypoxic
ischemic injury and infectious causes (Volpe et al.,
2006).
Two types of ACC can be distinguished morpholog-
ically: ACC type 1, in which axons are present but are
unable to cross the midline; they form large aberrant
fiber bundles (Probst bundles) along the medial hemi-
spheric walls and ACC type 2, apparently less frequent,
in which axons fail to form; therefore no Probst bundles
are found.

Sonographic findings: Prevalence of the ACC varies

in different studies, depending on the population studied
and the diagnostic criteria: it ranges between 0.3 and
0.7% in the general population and between 2 and 3%
in the developmentally disabled population (Jeret et al.,
1985–1986).
The demonstration of the CC is possible with ultra-
sonography (US), but requires some degree of technical
skill as it is not depicted using the standard axial planes
but coronal and particularly sagittal ones. In fetuses
in vertex presentation the transvaginal approach is pre-
ferred (Monteagudo et al., 1991; Malinger et al., 1993);
in breech presentation a transfundal approach is sug-
gested. Recently, the use of 3D multiplanar technique
has also been proposed (Pilu et al., 2006) (Figure 3), as
it offers a more accurate identification of the mid-sagittal

Figure 2—MRI mid-coronal image of a 26-week normal fetal brain

T2-weighted HASTE image. (a)White arrows indicate the fibers of the
genu forming the forceps minor because of their shape as they come
from the anterior frontal lobes; they connect the prefrontal cortices.
C, cavum septi pellucidi. (b) White arrows indicate the fibers of the
splenium, forming the forceps major as they spread posteriorly

plane, whereas navigation in the other two simultaneous

Figure 1—Mid-sagittal view of the brain in a 23-week fetus showing
the entire corpus callosum (CC). R, rostrum; G, genu; B, body; S,
splenium; csp, cavum septi pellucidi
orthogonal planes may permit a better evaluation of the
midline prosencephalic structures.
While using axial planes, the diagnosis is based in
the presence of some indirect signs. As the CC shares
with the SP a common anatomic and embryogenetic
formation, complete ACC is commonly associated with a
hypoplastic or absent CSP. Hence, at the mid-trimester
anomaly scan, ACC may be suspected when the CSP
is not visualized on the axial transthalamic view. The
suspicion of ACC is further supported by the recognition
of the following indirect signs (Figure 4):

Copyright  2009 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 340–354.
DOI: 10.1002/pd
342 P. VOLPE ET AL.

Figure 3—Multiplanar analysis of the ultrasound (US) volume obtained from an axial trans-ventricular view of a 23-week fetal brain. The A
plane corresponds to the axial plane, B to the coronal plane, and C to the sagittal plane. In C, the reconstructed median plane allows recognition
of the CC (arrow) as an anechoic stripe within a thin echogenic contour that separates it from the underlying cavum septi pellucidi (csp). The
position of the reference dot is within the CSP

Figure 4—Agenesis of the corpus callosum (ACC): indirect signs. (a) Axial scan of a 21-week fetal brain demonstrating the absence of the
cavum septi pellucidi (arrow) and the teardrop aspect of the lateral ventricle due to the dilatation of the atria and occipital horns (colpocephaly).
(b) Axial scan of a 22-week fetal brain showing the upward displacement of the third ventricle (3v) and colpocephaly. Interhemispheric fissure
appears wider than usual without evidence of the cavum septi pellucidi (arrow)

- colpocephaly (dilatation of the atria and occipital
horns), due to the absence of the splenium and to
a defect of the intrinsic association bundles of the
occipital lobe;
- increased separation of the hemispheres with the bodies
of the lateral ventricles parallel to each other and
shifted laterally;
- an abnormal third ventricle, which extends upward
between the lateral ventricles (LV ) (in 50–60% of
cases).
On the coronal sections of the fetal brain the indirect
signs are mainly characterized by the aspect of the
frontal horns, which are separated more than usual and
their inner walls are concave medially (Figure 5). This
is due to the compression exerted by a conspicuously
large longitudinal bundle of fibers that represent the
callosal fibers, which fail to cross the hemispheres
and instead are rerouted parasagittally, parallel to the
midline. This abnormal bundle, called the longitudinal
bundle of Probst, runs parallel to the medial walls of the
LV and invaginates their medial borders at the level of
the frontal horns.
All these indirect signs can only be individually
present and this probably in part explains the frequent

Copyright  2009 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 340–354.
DOI: 10.1002/pd
 DISORDERS OF PROSENCEPHALIC DEVELOPMENT 343

Figure 5—(a) Mid-coronal view of the brain in a 23-week normal fetus showing the normally developed frontal horns, genu (arrow) and cavum
septi pellucidi (csp). (b) Agenesis of the corpus callosum. Coronal scan of a 30-week fetal brain demonstrating absence of the genu and an
increased distance between the frontal horns (arrows). The inner walls of the frontal horns are concave medially due to the medial compression
exerted by the Probst bundles. Together with the lumen of the third ventricle, this makes up the typical appearance of a ‘bull’s head’

Figure 6—(a) Mid-sagittal scan of the brain in a 31-week fetus with agenesis of the corpus callosum (ACC) demonstrating the absence of CC
and of the CSP. At this advanced gestation age, an atypical radiating appearance of the median sulci, which converge toward the third ventricle
(3v) can also be seen. In this view, usually no cingulated gyrus is recognized, or it is everted. (b) Mid-sagittal view of the brain in a 31-week
normal fetus showing ultrasound (US) appearance of cingulate sulcus (arrows) and gyrus, above the corpus callosum (csp, cavum septi pellucidi)

false negative diagnosis of ACC. A definitive diagno-

sis of ACC relies on recognition of the direct signs
(Pilu et al., 1993; Moutard et al., 2003; D’Addario et al.,
2005), which consist of the demonstration of the absence
of the CC on mid-sagittal and coronal views of the fetal
brain. In particular, the mid-sagittal plane will demon-
strate absence of the CC and, in advanced gestation
or post-natally, an atypical radiating appearance of the
median sulci, which converge toward the third ventricle
(Figure 6). In this view, usually no cingulated gyrus can
be recognized (Figure 6), or it appears incomplete.
As already mentioned, ACC may also be partial. In
this case, the sonographic findings are more subtle than
those associated with the complete form. When the
CC is hypogenetic, it is usually the posterior portion
that is affected (the posterior body and the splenium)
(Figure 7); in this situation, the CSP is present (Volpe
et al., 2006), and often the only indirect sonographic
sign is a mild colpocephaly. Sometimes, the indirect
signs of PACC may also be completely absent (Volpe Figure 7—Mid-sagittal scan of the brain in a 22-week fetus with
et al., 2006). A sagittal view is the only way to reach partially absent corpus callosum (PACC) showing partial formation
of the corpus callosum (CC). Genu and anterior part of the body (CC)
the diagnosis, visualizing a small CC that is lacking are present, whereas the posterior part of the body and the splenium
the posterior part and only partially surrounds the third are absent. Cavum septi pellucidi (CSP) is present but smaller than
ventricle (Figure 7). usual. The CC/CSP complex does not entirely cover the third ventricle
In less frequent cases, the remaining structure is the (3v) but only reaches about midway
genu; it can appear thin and barely discernible with

Copyright  2009 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 340–354.
DOI: 10.1002/pd
344 P. VOLPE ET AL.

Figure 8—(a) Mid-sagittal view of a 22-week normal fetal brain. Color Doppler demonstration of anterior cerebral artery (ACA) branching giving
rise to the pericallosal artery (PA). CSP, cavum septi pellucidi. (b) Partially absent corpus callosum (PACC). Mid-sagittal view of a 22-week
fetal brain. The small corpus callosum (CC) is highlighted by the course of the pericallosal artery (PA). In fact the PA closely follows the genu
and the anterior part of the CC body but loses its normal course where the CC disappears; it takes an upward posterior oblique direction. CSP,
cavum septi pellucidi; ACA, anterior cerebral artery. (c) Agenesis of the corpus callosum (ACC). Mid-sagittal view of a 30-week fetal brain
demonstrating the absence of the PA; its classical loop is not seen

gray scale imaging and can be identified only when

highlighted by the course of the pericallosal artery (PA).
The use of Color Doppler, in case of ACC, allows
to demonstrate that the semicircular loop, normally
formed by PA along the superior surface of CC, is lost
(Figure 8). This sign may help to make the diagnosis of
ACC. Its value is yet greater in the case of PACC; in this
case the PA closely follows and depicts the small anterior
part of CC (Figure 8), often difficultly discernible with
gray scale imaging. Its following course is then lost,
being absent in the posterior part of CC.
Fetal magnetic resonance imaging (MRI) is particu-
larly useful in demonstrating possible additional cerebral
anomalies such as late sulcation, migration anomalies,
and heterotopia. However, in most cases, the presence
of these anomalies can be recognized only from the late
second trimester onward, with late development of the
sulci and gyri.
Midline interhemispheric cysts (Figure 9) associated
with ACC are often considered as mere extensions of the
ventricular system. These cysts have a variable appear-
ance and can be divided into two main categories: one in
which the ‘cysts’ are herniations of the ventricular sys-
tem, representing the dorsal expansion of the roof of the
third ventricle, and the other in which they are clearly
separated from the ventricles. In the latter case, subcor-
tical heterotopia is often associated (Barkovich, 2000).
Another median anomaly that may be associated with
ACC is an intracranial lipoma, visible only in the third
trimester as a hyperechogenic image under the inferior
part of the interhemispheric scissure.
Prognosis: Although the overall prognosis of ACC
remains controversial, several studies have reported a
worse prognosis in the presence of additional anoma-
lies (Shevell et al., 2002; Moutard et al., 2003; Volpe
et al., 2006). In fact ACC is often associated with major
cerebral and/or extracerebral malformations, including
50 different human congenital syndromes, and metabolic
diseases (Tables 1, 2, 3, 4). The risk of associated
brain anomalies, such as Dandy–Walker complex, gyral
anomalies, and neuronal heterotopia, is extremely high
(upto 80%). The risk of associated extra-CNS abnor-
malities is high (upto 60%), including congenital heart
disease, skeletal and genitourinary defects.
Figure 9—Mid-sagittal scan of the brain in a 32-week fetus with
agenesis of the corpus callosum (ACC) showing the absence of the
corpus callosum (CC) and the presence of an interhemispheric cyst
(arrows) communicating with the third ventricle. The cyst is usually
evident only in the third trimester
To rule out an associated abnormality the evaluation
should include a detailed neurosonographic examination,
a sonographic search for non-central nervous system
(CNS) anomalies, fetal echocardiography, karyotype
evaluation, TORCH tests, and in cases with apparent
isolated ACC, a fetal brain MRI from late second
trimester onward.
In the cases of apparently isolated ACC, it appears to
carry a better prognosis (Pilu et al., 1993; Moutard et al.,
2003; Volpe et al., 2006). However, caution must be
adopted in these cases when assessing the fetal/neonatal
prognosis. In fact, considering the small number of fetal
series reported in the literature, no general conclusions
can be drawn, although some interesting points can be
made.
The first issue is that other CNS malformations
(especially gyral anomalies and heterotopia) or extra-
CNS anomalies can be present even when ACC is
apparently isolated on ultrasound/MRI, especially if
performed at 20–22 weeks. The systematic use of late
fetal MRI could improve the detection of associated
malformations of cortical development (MCD) in these

Copyright  2009 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 340–354.
DOI: 10.1002/pd
 DISORDERS OF PROSENCEPHALIC DEVELOPMENT 345
Table 1—Causes and conditions associated with ACC cases (Moutard et al., 2003). For this reason some
authors (Salomon and Garel, 2007) prefer to wait until
Cause/Condition Diagnostic aids
the beginning of the third trimester (28–32 weeks)
Chromosomal abnormalities because some sulci are not visible before 26–28 weeks,
Trisomy 18 while narrow pericerebral spaces hinder visibility of
Trisomy 8 the sulci after 34 weeks. However, parental anxiety
Trisomy 21 Fetal and the legal age limit for termination of pregnancy
Trisomy 22 karyotyping (TOP) where the scan is being performed may lead
Others: other trisomies, deletions,
to the MRI examination being performed at an earlier
translocations, duplications
gestational age.
Cryptic unbalanced aberrations FISH, CGH array,
parental
The second point is that, regardless of the associated
karyotyping anomalies, significant neurodevelopmental delay devel-
Genetic syndromes ops in a consistent proportion of cases (15–36%) (Pilu
Autosomal dominant Associated US et al., 1985; Moutard et al., 2003; Volpe et al., 2006;
Autosomal recessive features—family Fratelli et al., 2007), even if complete ACC is confirmed
X-linked history (see to be isolated post-natally. The same also applies to iso-
Tables 2–4) lated PACC.
Enviromental factors A final point that should be made is that even
Alcoholism Prenatal when the outcome is good, subtle neuropsychologic,
Maternal rubella history perceptual, and motor defects can emerge later in life,
Metabolic disorders as all individuals with complete or partial ACC have
Adenylocuccinase deficiency some neuropsychological symptoms. The presence of
Adipsic hypernatremia defects in the transfer of information should be taken
B-hydroxyisobutyryl coA deacylase into account in counseling when complete or partial
deficiency
Maternal diabetes
ACC is diagnosed in fetal life (Moutard et al., 2003).
Glutaric aciduria type II Considering the presence of neurosensorial information
Histidinemia Family history transfer defects, no significant differences seem to exist
Hurler syndrome and physical between PACC and complete ACC in terms of the
Leigh syndrome examination at performance accuracy of the somatosensory functions,
Menkes syndrome birth while response time was significantly shorter in PACC
Neonatal adrenoleukodystrophy
Nonketonic hyperglycinemia
than in complete ACC children (Friefeld et al., 2000).
Pyruvate dehydrogenase deficiency However, the clinical relevance of such deficits should
Zellweger syndrome not be exaggerated, because the functions of the CC

Table 2—Genetic syndromes with autosomal dominant inheritance associated with ACC

De novo Contributing
Genetic syndrome OMIM# Locus Gene inherit. factors Other possile US features
Apert’s s. #101200 10q25–q26 FGFR2 98% Paternal age Cranioynostosis, brachycephaly,
acrocephaly, frontal bossing, flat face and
occipit, mild ventriculomegaly, syndactyly,
polyhydramnios, increased NT
Basal cell nevus s. #109400 9q22.3 PTC 40% Paternal age Unilateral cleft lip, cleft palate,
(Gorn s.) hydrocephalus
Greig cephalo- #175700 7p13 GL13 Few — Pre- and postaxial polydactyly syndactyly,
polysyndactyly macrocephaly
s.
Lenz–Majewski s. 151050 — — — — Prominent forehead, hypertelorism,
abnormalities of the digits (cutaneous
syndactyly etc.), thick ribs/clavicles
Miller–Dieker s. #247200 17p13.3 LIS1 44% — Lissencephaly,
microcephaly,polyhydramnios mild
ventriculomegaly, CHD, omphalocele,
IUGR
Mowat–Wilson s. #235730 2q22 ZFHX1B — — Microcephaly, megacolon, hypertelorism,
CHD
Opitz GBBB s. %145410 22q11.2 — — — Hypertelorism, facial cleft, CHD,
hypospadia, anal atresia
Rubinstein–Taybi #180849 16p13.3 REBBP Vast majority — CHD, spina bifida, 5th finger clinodactyly,
s. overlapping toes, polihydramnios
CHD, congenital heart disease; NT, nuchal translucency.

Copyright  2009 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 340–354.
DOI: 10.1002/pd
346 P. VOLPE ET AL.

Table 3—Genetic syndromes with autosomal recessive inheritance associated with ACC

Genetic syndrome OMIM# Locus Gene Other possile US features

Acrocallosal s. #200990 7p13 GLI3 Postaxial polydactyly, hallux duplication,
hypertelorism, macrocephaly, prominent forehead,
ventriculomegaly
Andermann s. #218000 15q13-q14 SLC12A6 Commonly no prenatal US findings
COFS s.me #214150 10q11 ERCC6 Microcephaly, arthrogryposis, micrognathia
Coffin–Siris s. %135900 — — Absence of distal phalanges, IUGR
Congenital ocular %257550 2q13 — Commonly no prenatal US findings
motor apraxia (Cogan
s.)
Dincsoy s. 601016 — — Hypotelorism, short limbs, camptodactyly,
overlapping fingers, ambiguous genitalia
Fryns s. %229850 — — Diaphragmatic hernia, cystic hygroma, CHD, cleft
palate
Fukuyama congenital #253800 9q31 FCMD Cerebral/cerebellar cortical dysplasia
muscular dystrophy (polymicrogyria, pachygyria, and agyria)
Hydrolethalus s. #236680 11q24.2 D211G Hydrocephalus, abn. gyrations, facial cleft,
micrognathia, micropthalma, CHD, polydactyly,
club foot, polyhydramnios
Joubert s. %213300 9q34.3 — Vermis hypoplasia, hypertelorism, D-W m,
occipital encephalocele, polydactyly (hands/feet),
cystic kidneys
Leprechaunism #246200 19p13.2 — IUGR
(Donohue s.)
Lowry–Wood s. %226960 — — Microcephaly
Lyon s. 225740 — — Cardiomyopathy, cataracts
Marden–Walker s.me %248700 — — Microcephaly, cerebellar/vermis hypoplasia, D-W
m, cleft palate, micrognathia, CHD,
camptodactyly, aracnodactyly, talipes, absent
clavicle, cystic kidneys, IUGR
Meckel–Gruber s. #249000 17q22-q23 — Occipital cephalocele, cystic kidneys, polydactyly,
type 1 oligohydramnios
Microcephalic %210710/%210730 2q14.2- — Short limbs, microcephaly, vermis agenesis, cleft
osteodysplastic q14.3/unknown vertebral arches, platyspondyly
primordial dwarfism
type I/III
Muscle-eye-brain #253280 19q13.3, POMGNT1 Mild-moderate cerebellar/vermis hypoplasia
(MEB) disease 1p34-p33
Neu–Laxova s. %256520 — — Cerebral/cerebellar hypoplasia, microcephaly,
lissencephaly, micrognathia, exophthalmos,
cataracts, microphtalmia, short limbs, syndactyly,
IUGR, polyhydramnios, short cord, small placenta
Peters plus s. #261540 — — Prominent forehead, hypertelorism, micrognathia,
short limbs, CHD, hydronephrosis, facial cleft,
IUGR
Septo-optic dysplasia #182230 3p21.2-p21.1 HESX1 Hypoplastic optic nerves, ASP, schizencephaly
Shapiro s. — — — Commonly no prenatal US findings
Smith-Lemli-Opitz s. #270400 11q12-q13 Multigenic Microcephaly, syndactyly, facial cleft, genital
abnormalities, increased NT
Thrombocytopenia- %274000 1q21.1 — Radial agenesis, lower limb/renal anomalies,
bsent radius s. CDH, hypoplasia of the vermis
Toriello–Carey s. %217980 — — Cerebellar hypoplasia, hydrocephalus, CHD,
IUGR, polyhydramnios
Vici s. %242840 — — Bilateral cataract, cleft lip and palate,
cardiomyopathy
Walker–Warburg s. #236670 19q13.3, FKTN Lissencephaly type II, D-W m, microphtalmia,
14q24.3, optic nerve hypoplasia, cephalocele, microcephaly,
9q34.1, 9q31 hydrocephaly, ventriculomegaly, cataract,
etc concentric ring in the vitreous body (retinal
detachment), lipoma of the CC, anal atresia
Warburg Micro s. #600118 2q21.3 RAB3GAP Microcephaly, congenital cataract, hypogenitalism
in males
CHD, congenital heart disease; D-W m, Dandy–Walker malformation.

Copyright  2009 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 340–354.
DOI: 10.1002/pd
 Table 4—X-linked genetic syndromes associated with ACC

Genetic syndrome OMIM# Locus Gene D/R Males/Females Other possile US features
Aicardi s. %304050 Xp22 — D Lethal in ♂ (only male Micro-ophtalmia, CPCs, CPP, D-W m,
case referred: XXY) facial cleft

Copyright  2009 John Wiley & Sons, Ltd.

ATRX s. (X-linked #301040/ Xq13/16p ATRX gene R — Microcephaly, genitalia abnormalities,
type/deletion type) #141750 mutation/16p hemivertebra, renal agenesis,
deletion hydronephrosis
Craniofrontonasal s. #304110 Xq12 EFNB1 gene D ♀ more severely ♂&♀: hypertelorism, toes syndactyly,
mutation affected than males clinodactyly ♀ only: craniosynostosis,
brachycephaly, frontal bossing syndactyly
FG s. 1 #305450 Xq12-q21.31 MED12 gene R ♀ unaffected or with Hypertelorism, anal atresia, clinodactyly,
(Opitz–Kaveggia s.) mutation carrier manifestations syndactyly, facial cleft, cardiac
abnormalities
Hirschsprung disease #142623 Polygenic (incl. X: — D/R/ ♂/♀: 3 : 1–5 : 1 Dilated discending colon, multiple dilated
q28) poly loops, hyperechogenic bowel
HSAS (MASA) s. #307000 Xq28 L1CAM R ♀ unaffected or with Hydrocephalus, flexed thumb, absent SP,
(X-linked hydrocephalus) carrier manifestations porencephalic cyst
Hypohidrotic ectodermal #305100 Xq12-q13.1 — R — Low nasal bridge, small nose, prominent
dysplasia sopraorbital ridges
Incontinentia pigmenti #300337 Xp11 X/autosome D Almost always sporadic Brachycephaly, micropolygyria
transloc.or and present in mosaic
ring-X form
Lujan–Fryns s. #309520 Xq13 MED12 gene R Higher penetrance and Commonly no prenatal US findings
mutation expressivity in ♂
DISORDERS OF PROSENCEPHALIC DEVELOPMENT

Opitz s.me, X-linked #300000 Xp22 MID1 R Minor expression in ♀ (See autosomal dominant type of Opitz s.)
Orofacial digital s. type 1 #311200 Xp22.3-p22.2 CXORF5 D Lethal in ♂ Median cleft lip, cleft palate, digit
abnormalities,
Proud s. #300004 Xp22.13 ARX D Variable expression in ♀ Ambiguous genitalia
XLIS s. #300067 Xq22.3-q23 DCX — Milder in ♀ Microlyssencephaly-microcephaly-
pachygyria-agyria, cerebellar/vermis
hypoplasia, ambiguous genitalia
CPCs, Choroid plexus cysts; CPP, Choroid plexus papilloma; D-Wm, Dandy-Walker malformation

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347
348
are not completely understood (Corballis et al., 2004)
and it is difficult to correctly assess the neuropsycologic
status of individuals with complete ACC/PACC and
normal-range IQs, and the role of possible compensatory
mechanisms (Volpe et al., 2006).
Nevertheless, a protracted follow-up (until around six
years of age) is important to update the neurodevelop-
mental status of these patients, especially with regard to
social interactions and school performance, in order to be
able to provide better prognostic information to families.
Absent septum pellucidum and septo-optic
dysplasia
Septal Agenesis is a rare brain abnormality that occurs
in 2–3/100 000 individuals in the general population. It
can be isolated or part of developmental brain anomaly,
namely SOD, HPE, ACC and malformations of corti-
cal development. Such anomalies can be subtle leading
to difficulties in prenatal diagnosis and management.
In addition, secondary disruption of SP due to severe
hydrocephaly has been reported (Malinger et al., 1993).
When associated with optic nerve hypoplasia, ASP is a
classical feature of SOD. SOD was first described by
De Morsier (De Morsier, 1956) in an autopsy series
of 36 patients; it is a highly heterogeneous condition
comprising a variable phenotype of optic nerve hypopla-
sia, absent SP and pituitary hypoplasia, with conse-
quent endocrine deficits. In a discrete number of cases,
schizencephaly, ACC or other cortical malformations are
associated (SOD-plus). This apparent heterogeneity has
resulted in some disagreement as to whether SOD should
be regarded as a single precise entity or, rather, a group
of heterogeneous cases.
Pathogenesis
The majority of cases of SOD are sporadic and several
etiologies have been suggested to account for the patho-
genesis of the condition. However, a number of familial
cases have been described and the identification of muta-
tions in key developmental genes including HESX1,
SOX2 and SOX3 in patients with SOD and associated
Figure 10—(a) Mid-coronal view of the brain in a 23-week normal fetus showing the normally developed frontal horns, genu (CC) and cavum
septi pellucidi (csp). (b) SOD. Mid-coronal plane of a 29-week fetal brain showing the absence of the cavum septi pellucidi with communicating
frontal horns. The typical aspect of the downward point of the frontal horns is clearly seen (arrows). The genu is normally developed [corpus
callosum (CC)]. (c) Lobar holoprosencephaly (HPE). Mid-coronal plane of a 30-week fetal brain showing the absence of the cavum septi pellucidi
and of the genu. The frontal horns are fused centrally, as well as the fornices (arrow) that form a thick fascicle
Copyright  2009 John Wiley & Sons, Ltd.
P. VOLPE ET AL.
phenotypes suggests that a genetic causation is likely in
the more common sporadic cases of the condition. The
precise etiology of SOD is most likely multifactorial,
involving contributions from environmental factors in
addition to an important role for crucial developmental
genes (Kelberman and Dattani, 2008).
Sonographic findings
Absent SP with communicating frontal horns may indi-
cate SOD or lobar HPE, or it may even be an isolated
anomaly (Lepinard et al., 2005; Malinger et al., 2005;
Pilu et al., 2005). On coronal view, the sonographic
aspect of absence of SP results in a squared appear-
ance of the frontal horns with inferior pointing. If the
interhemispheric fissure is normally developed, the ante-
rior CC and anterior cerebral arteries are normal in
shape/position and the fornices are not fused; this is sug-
gestive of ASP without HPE, in which case SOD is then
suspected (Figure 10).
The differential diagnosis between SOD and isolated
agenesis of the SP may be attempted by:
- evaluation of maternal urine and serum estriol levels;
- fetal blood assays for growth hormone, adrenocortico-
tropic hormone (ACTH) and prolactin;
- visualization of the optic nerve size at the third
trimester, as depicted by MRI in a search for optic
nerve hypoplasia.
It must be kept in mind that hypoplasia of the optic
nerves and/or chiasma may be difficult to assess even
with MRI and sometimes may develop only after birth.
However, in the presence of hypoplastic optic chiasma
and/or schizencephaly, the diagnosis of SOD or SOD-
plus has to be suspected and should be confirmed by
the presence of maternal and fetal endocrinological
deficiencies characterized by low maternal serum and
urinary estriol levels and fetal growth hormone, ACTH
and thyroid stimulating hormone deficiency (Lepinard
et al., 2005).
The onset and extent of hormonal disorders in SOD
patients vary considerably. In fact endocrinological defi-
ciencies are found in only 50–90% of cases during
Prenat Diagn 2009; 29: 340–354.
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 DISORDERS OF PROSENCEPHALIC DEVELOPMENT 349

infancy (Willnow et al., 1996). For this reason, despite Table 5—Causes and conditions associated with HPE
normal fetal pituitary function (and normal appearance
of the optic tract on fetal MRI), SOD cannot be com- Cause/Condition Diagnostic aids
pletely ruled out prenatally. However, in case of Septal Chromosomal abnormalities
Agenesis detected at mid-trimester, the assessment of Trisomy 13
fetal pituitary function should be incorporated into the Trisomy 18
diagnostic work-up, as its disorder, when present, rep- Tripoidy Fetal karyotyping
resents a typical sign of SOD. Others: Deletions
Duplications
Partial monosomy 14q
Prognosis Cryptic unbalanced FISH, CGH array, parental
aberrations karyotyping
The clinical presentation of SOD is variable: visual
disturbances may range from blindness to almost nor- Syndromic HPE
mal vision; hypothalamic-pituitary insufficiency, mainly Autosomal dominant Associated US features—family
history (see Table 7)
characterized by growth deficit and diabetes insipidus,
Autosomal recessive
is seen in two-thirds of patients. In case of SOD-plus, X-linked
seizures and/or spastic motor deficit are also present.
Non syndromic HPE
Isolated ASP is rare and thought to be asymptomatic.
However prenatal detection of an isolated ASP does not (See Table 6) Family history- examination of
necessarily preclude normal neurological clinical status the parents to identify
and this can be due to the presence of undetectable microforms of HPE and/or
parental mutation analysis
histopathological brain anomalies with US and MRI
(Belhocine, 2005). Enviromental factors
Retinoic acid
Ethyl alcohol
Disorders of prosencephalic cleavage Salicylates
Estrogen/Progestin
Holoprosencephaly Anticonvulsants Prenatal history
CMV
The term ‘holoprosencephaly’ refers to a group of com- Rubella
plex abnormalities of the brain resulting from incomplete Toxoplasma
division of the prosencephalon into two halves, usu- Metabolic disorders
ally associated with various facial anomalies (Cohen, Maternal diabetes Family history
2006; Dubourg et al., 2007; Orioli and Castilla, 2007;
Shiota et al., 2007). The incidence of HPE is 1 in
10 000–15 000 births; it is higher in spontaneous abor- (Croen et al., 1996; Olsen et al., 1997; Bullen et al.,
tion (Matsunaga and Shiota, 1977) (1 in 250) indicating 2001; Ong et al., 2007), most commonly trisomy 13.
that most HPE fetuses are aborted. Monogenic inheritance of non-syndromic HPE (Table 6)
The brain malformations, characterized by the fusion includes most commonly autosomal dominant transmis-
of the cerebral hemisphere along the midline associated sion with variable expressivity and incomplete pene-
with a number of midline anomalies, such as absence trance; autosomal recessive transmission and X-linked
of SP and CC, are commonly associated with facial transmission have been also reported. To date, nine
anomalies, ranging from anophthalmia, cyclopia or pro- genes and their mutations are known to cause HPE
boscis in the most severe cases, to midline cleft lip, a in the humans: SHH, PTCH, GLI2, ZIC2, TDGF1,
simple hypotelorism or even no anomalies in the less TMEM1, TGIF, FAST1 and SIX3 (Cohen, 2006; Orioli
severe HPE forms (Barkovich, 2000; Blaas et al., 2002; and Castilla, 2007; Shiota et al., 2007). Because vari-
Tortori-Donati et al., 2005; Dubourg et al., 2007). In ous pathways are linked to the sonic hedgehog (SHH)-
familial cases, HPE phenotypic spectrum is very large, signaling network, most of the mutations are interrelated.
ranging from severe cerebral malformations to micro- SHH protein seems to be a developmental regulator of
forms. This latter form can be defined by normal brain the ventral neural tube, important for its induction and
MRI in a patient with midline defects, including sin- differentiation. During the last 20 years, it has become
gle central maxillary incisor, ocular hypotelorism, iris clearer that a primary defect of induction and patterning
coloboma, flat nose, nasale pyriform aperture steno- of the rostral neural tube may be important and that the
sis, anosmia/hyposmia, bifid uvula, absent superior prechordal plate may play a major role in the genesis
labial frenulum, midface hypoplasia, sometimes with- of HPE. Aberrancies in ventral midline SHH-expressing
out mental retardation (Cohen, 2006; Dubourg et al., cells, or in the SHH pathway, both of which are critical
2007). to the normal development of the forebrain, appear to
play a pivotal role in this disorder.
Pathogenesis and classification: The etiology of HPE Cohen listed a large number of monogenic syndromes
is very heterogeneous (Table 5). The identified causes with HPE (Cohen, 2006) (Table 7).
are chromosomal, monogenic, and teratogenic. Chromo- Some environmental and metabolic factors have also
somal abnormalities are present in 24 to 47% of all cases been implicated in HPE. In fact diabetic embryopathy,

Copyright  2009 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 340–354.
DOI: 10.1002/pd
350
Table 6—HPE genetic mutations
Gene Locus Name
SHH 7q36-qter HPE3
ZIC2 13q32 HPE5
SIX3 2p21 HPE2
TGIF 18p11.3 HPE4
GLI2 2q14 HPE9
FAST1 (FOXH1) 8q24.3
PTCH1 9q22.3 HPE7
TDGF1 (CRIPTO) 3p23-p21
TMEM1 21q22.3 HPE1
MIH, midline interhemispheric; ACC, agenesis of the corpus callosum; nd, not determined.
retinoic acid embryopathy and fetal alcohol syndrome
have been reported with HPE.
Nevertheless, in about 70% of cases, the molecular
basis of the disease remains unknown, suggesting the
existence of several other candidate genes or environ-
mental factors. Consequently, a ‘multiple-hit hypothe-
sis’ of genetic and/or environmental factors has been
proposed to account for the extreme clinical variability
(Dubourg et al., 2007).
The most widely accepted classification of HPE rec-
ognizes three major varieties: the alobar, semilobar,
and lobar types, according to the severity of the mal-
formation with respect to the brain (and the face),
which follows an anterior-to-posterior gradient with the
anterior portion of the brain being least well formed
(Figure 11). However, there are no precise boundaries
between the three variants, and intermediate cases may
be identified. Therefore HPE should be viewed as a
continuous spectrum ranging from the most severe alo-
bar forms, in which the neonate has a very short life
span, to the milder forms, in which the anomaly may
be discovered incidentally. Although this categorization
is useful to give an idea of the severity of the picture,
it has become apparent that several important features,
such as some associated cortical anomalies, cannot be
completely incorporated into this classification scheme.
Recently, another variant of HPE has been described: the
middle interhemispheric (MIH) HPE (syntelencephaly),
mainly affecting the dorsal forebrain, which represents
an exception to this anterior-to-posterior rule (Simon
et al., 2002) and could be a separate form (Figure 11).
In alobar HPE, the prosencephalon fails to cleave
sagittally into cerebral hemispheres, transversely into
telencephalon and diencephalon and horizontally into
olfactory tracts and bulbs. It is characterized by a single
primitive cerebral ventricle continuous with a large
dorsal cyst. No midline structures, including the falx
cerebri, the interhemispheric fissure, the SP, the CC and
the third ventricle, are present and the thalami are fused
on the midline.
Copyright  2009 John Wiley & Sons, Ltd.
P. VOLPE ET AL.
Type of HPE and clinical findings OMIM
∗
From cyclopia/alobar HPE to normal 600725, #142945
∗
Alobar, semilobar, MIH, microcephaly, 603073, #609637
hydrocephaly, ACC, normal or mild
facial abnormalities
∗
Semilobar, alobar, cyclopia, 603714, #157170
microcephaly, craniofacial defects
∗
Lobar, semilobar, ACC, microcephaly, 602630, #142946
craniofacial defects
Alobar, pituitary anomalies, #610829, ∗ 165230
microcephaly, hydrocephalus,
craniofacial defects
Nd #603621
∗
From semilobar to lobar with 601309, #610828
craniofacial defects to normal
Minor craniofacial defects, +187395
microcephaly, single ventricle
∗
Alobar 602103
The semilobar variety is characterized by the presence
of rudimentary lateral ventricles with sketchy posterior
horns, partial development of the interhemispheric fis-
sure and of the falx cerebri, which are present only
posteriorly. Partial fusion of the thalami and partial age-
nesis of the CC are present. SP is absent.
The lobar variety is characterized by partial fusion
of the frontal horns, which show ample communication
with the third ventricle, partial agenesis of the CC and
absence of the SP.
It has to be pointed out that HPE is the only brain
malformation described in which the posterior CC forms
in the absence of anterior callosal formation.
Sonographic findings: Prenatal diagnosis of HPE by
US has been reported (Figure 12) and criteria for diag-
nosis are well established (Pilu et al., 1987). Early diag-
nosis of alobar HPE during the first trimester has been
reported based on the visualization of a single ventri-
cle (Turner et al., 1999; Blaas et al., 2000) (Figure 12).
The visualization of cerebral ventricular abnormalities,
on axial plane of the fetal brain, and of facial anoma-
lies are usually the first step in the diagnostic pro-
cess (Paladini and Volpe, 2007). However a definitive
diagnosis may still be difficult, particularly in cases
of lobar HPE. In fact the diagnosis of the lobar form
requires a mid-coronal plane to demonstrate the absence
of the CSP and the central fusion of the frontal horns
(Figure 10), which communicate with the third ventricle
(Pilu et al., 1992). The aspect of the frontal horns, ‘a
box-like squared shape’, on coronal section resembles
that seen in SOD (Figure 10). The presence of fused
fornices and the absence of a normally developed inter-
hemispheric fissure in between the anterior hemispheres
helps to differentiate lobar HPE from SOD (Figure 10).
Recently, an additional sonographic sign has been used
to differentiate between lobar HPE and SOD: in lobar
HPE, the anterior cerebral artery is often pushed ante-
riorly alongside the frontal bone by an abnormal bridge
of cortical tissue between the two frontal gyri (Bernard
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 DISORDERS OF PROSENCEPHALIC DEVELOPMENT 351
Table 7—Genetic syndromes associated with HPE

Genetic syndrome OMIM# Locus Gene Other possile US features

Autosomal dominant Dysgnathia complex
Kallman s.
Pallister-Hall s.
Rubinstein-Taybi s.
Steinfeld s.
Thanatophoric dysplasia type II #187 601
Autosomal recessive Spinocerebellar ataxia (Van
Bogaert-Martin s.)
Ivemark s. (Heterotaxy and
HPE)
Hydrolethalus s.
Lambotte s.
Meckel-Gruber s. type 1
Pseudotrisomy 13 s.
Smith-Lemli-Opitz s.
XK aprosencephaly s.
X-linked Aicardi s. (D)
Ectrodactyly (R)
Fetal hypokinesia/akinesia (R)
D/R, dominant/recessive; poly, polygenic pattern of inheritance; CPC, chorioid plexus cyst; CPP, chorioid plexus papilloma; D-W m, Dandy-
Walker malformation.
%202 650 Unknown Mandibular hypoplasia or
agenesis, skeletal and
genitourinary, CHD, situs
inversus, polyhydramnios
#147 950 8p11.2-p11.1 PROKR2 Midline facial cleft
#146 510 7p13 GLI3 Micrognathia, absent lung,
CHD, renal abnormalities, and
atresia, anomalies of the digits,
mild IUGR
#180 849 16p13.3 REBBP CHD, spina bifida, 5h finger
clinodactyly, overlapping toes,
polihydramnios
184 705 Unknown Radial/ulnar hypoplasia, absent
thumbs, midline cleft lip and
palate, CHD, renal
abnormalities, absent
gallbladder
FGFR3 Straight and relatively normal
femours but severe cloverleaf
scull
%271 250 6p23-p21 Commonly no prenatal US
findings
%208 530 Unknown Asplenia/polysplenia, situs
ambiguus CHD,
#236 680 11q24.2 HYLS1 Hydrocephalus, abnormal
gyrations, facial cleft,
micrognathia, micropthalma,
CHD, polydactyly, club foot,
polyhydramnios
245 552 Microcephaly, IUGR
#249 000 17q22-q23 Occipital cephalocele, cystic
kidneys, polydactyly,
oligohydramnios
Severe facial anomalies,
postaxial polydactyly,
#270 400 11q12-q13 Microcephaly, syndactyly,
genital abnormalities, facial
cleft
264 480 Severe facial anomalies,
postaxial polydactyly, CHD
%304 050 Xp22 Micro-ophtalmia, CPCs, CPP,
D-W m, facial cleft
300 571 Unknown Ectrodactyly, facial cleft,
hypertelorism, craniosynostosis,
radial agenesis
306 990 Unknown Microcephaly, IUGR

et al., 2002). This sign of a ‘snake under the skull’ is
clearly seen on the mid-sagittal view of the fetal brain
(Figure 13).
MRI is useful because it may allow the assessment of
the optic nerve at the third trimester. It does not reveal
optic nerve hypoplasia in lobar HPE, unlike in SOD. In
addition the fusion of the fornices as a linear structure
running down inside the third ventricle, typical of lobar
HPE, can be better demonstrated by MRI.
Differentiation between semilobar and lobar HPE can
be difficult, as no clear boundary exists between the two
forms. If the third ventricle is completely formed, when
some frontal horn formation is present and the splenium
and posterior part of the callosal body are completely
formed, the HPE variant can be classified as lobar.
In the case of HPE, sonographic assessment of the
fetal face is mandatory. The spectrum of facial anoma-
lies, caused by an abnormal development of the midline
structures, ranges from cyclopia to mild dysmorphisms.
The more severe the facial anomalies, the more pro-
nounced the brain lesion (DeMyer et al., 1964) (‘the face
predicts the brain’ approximately 80% of the time), but
the reverse is not always true: about 15–20% of alo-
bar HPE cases are associated with only minor dysmor-
phisms. The most frequent facial anomalies are usually
classified in the following main types: cyclopia, with

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DOI: 10.1002/pd
352 P. VOLPE ET AL.

Figure 11—Variants of holoprosencephaly (HPE), compared with the normal brain

Figure 12—(a) Alobar holoprosencephaly (HPE): axial scan of a 13-week fetal brain showing fused thalami (T), absence of the midline structures
and a monoventricular cavity. (b) Semilobar holoprosencephaly: axial scan of a 22-week fetal brain showing the interhemispheric fissure (arrow),
present posteriorly but absent anteriorly, creating a single ventricle

a single midline orbit or absent eyes; arhinia, with or
without a proboscis; ethmocephaly, with evident ocular
hypotelorism and a proboscis located between the eyes;
cebocephaly, with less pronounced ocular hypotelorism
and a nose with a single nostril; a median cleft lip and
palate, with premaxillary agenesis; isolated premaxillary
agenesis and slight anomalies that cannot be detected by
ultrasound (e.g. a single central incisor).
Management and prognosis: HPE is frequently asso-
ciated with anomalies involving the CNS (microcephaly
and Dandy–Walker malformations) the heart, the skele-
ton, and the gastrointestinal tract.
When an HPE is detected in a fetus, karyotyping
should always be performed. In addition, the high risk
of syndromic HPE strongly supports a careful search for
additional structural anomalies.
If the fetal karyotype is normal, the parents should
be referred for genetic counseling, including a detailed
family history (with emphasis on pregnancy loss and
neonatal deaths), clinical examination to identify micro-
forms of HPE, and parental mutation analysis. In case
of fetal abortion, a post-mortem examination should also
be performed. Genetic review is particularly important
in women who have a euploid fetus with HPE to ade-
quately counsel and estimate the risk of recurrence in a
subsequent pregnancy, as well as initiating appropriate
molecular studies. Identification of mutations responsi-
ble for HPE can confer significant recurrence risks, upto
a 20%, in a clinically normal family (David et al., 2007).
In the severest forms of HPE, the neurologic deficit
is already evident in the neonatal period, in the form of
generalized hypotonia, seizures, feeding problems and
mental retardation. Endocrine disorders, such as diabetes
insipidus and growth hormone deficiency are commonly
associated.
Although many fetuses with HPE miscarry sponta-
neously, there is a common misconception that children

Copyright  2009 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 340–354.
DOI: 10.1002/pd
 DISORDERS OF PROSENCEPHALIC DEVELOPMENT
Figure 13—(a) Color Doppler demonstration of anterior cerebral artery (ACA) branching in a 24-week normal fetus and giving rise to the
pericallosal artery (PA). (b) Lobar holoprosencephaly in a 25-week fetus. The anterior cerebral artery branching (arrows) is pushed externally
alongside the frontal bone (sign of a ‘snake under the skull’) by the abnormal bridge of cortical tissue between the two frontal gyri (arrowheads)
with HPE do not survive beyond infancy. While this
is the case for the severest forms of HPE, a significant
proportion of patients with milder forms of HPE will sur-
vive into childhood and beyond (Plawner et al., 2002).
Life span is generally shorter if there are chromosomal
abnormalities
Among affected patients with a normal karyotype, an
inverse relationship exists between the severity of the
facial phenotype and length of survival.
- Infants with cyclopia or ethmocephalia generally do not
survive beyond age one week (Croen et al., 1996).
- Approximately 50% of children with alobar HPE die
before age four to five months and 20% live past the
first year of life (Barr and Cohen, 1999).
- More than 50% of children with isolated semilobar
or lobar HPE without associated significant malfor-
mations of other organs are alive at age 12 months
(Olsen et al., 1997; Barr and Cohen, 1999). Almost
all have apparently normal vision and hearing (Barr
and Cohen, 1999).
A discrete number of patients with isolated milder
form of HPE survive into the teenage years and were
able to speak and function with mild cognitive impair-
ment (Plawner et al., 2002).
In conclusion, while counseling families of fetuses
with HPE, it is important to point out the poor prognosis
of cases affected by the severest forms and/or with
associated significant abnormalities. However in case of
isolated forms of HPE, it is important to recognize the
relatively long survivals in milder forms.
CONCLUSION
In recent years, molecular analyses have shed light on
the contribution of major genes to the differentiation and
patterning of the fetal brain. However the pathogenesis
of cerebral midline anomalies is not fully understood.
Fetal cerebral midline anomalies can be accurately
diagnosed by prenatal neurosonography. Fetal MRI may
help in looking for MCD associated with agenesis of
CC and ASP. Differential diagnosis between SOD and
Copyright  2009 John Wiley & Sons, Ltd.
353
ASP can be extremely difficult even through MRI. In
the future new developments in molecular diagnosis and
new fetal MRI sequence may assist this task.
It is clear that fetal neurosonographers must work
with a team that includes neuroradiologists, pediatric
neurologists, geneticists and neuropathologists in order
to provide the most accurate counseling to the parents.
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DOI: 10.1002/pd