Janica E. Walden, MD
Neuroradiology
University of North Carolina
Holoprosencephaly (HPE)
 Spectrum of congenital structural forebrain anomalies
defined by different degrees of frontal lobe fusion
 Impaired midline cleavage of the embryonic forebrain
 “Face predicts brain”: severe midline anomaly = severe
HPE
 Clinical severity relates to degree of hemispheric and
deep gray nuclei fusion
Etiology & Pathology
 Normal prosencephalic cleavage occurs at 4-6 weeks
 HPE: disruption in dorsoventral axis patterning of
secondary prosencephalon,
 Result of mutations affecting signaling genes (Sonic
hedgehog gene) which regulate neural tube patterning.
 Extreme hypoplasia of neocortex
 Dorsal cyst (especially in association with non-cleaved
thalami) thought to represent expansion of partially
blocked posterodorsal 3rd ventricle
 Variable degree of fusion of diencephalon & basal
ganglia/thalamus with incorporation into upper brainstem
Epidemiology
 Occurs in 1 to 1.4 per 10,000 live births
 More common in early embryogenesis with high
spontaneous miscarriage rates
 Maternal factors include alcohol use, diabetes, retinoic
acid
 1% risk to infants of diabetic mothers (200-fold
increased risk than that of general population)
 Male: female ratio = 1.4: 1
Facial Anomalies
 Severe facial anomalies correlate with severity of HPE
in 80%
 +/- midline clefting
 premaxillary agenesis if severe
 absent superior frenulum
 +/- central incisor
 proboscis
 single nare; single nasal bone/absent inter-nasal sutures
 caudal metopic suture
 infants of diabetic mothers may have alobar HPE with
near-normal facies
Alobar HPE: Note
hypotelorism,
hypoplastic nose with
single nostril, small low
set ears.
Clinical Features
 Most severe (classic alobar HPE) features include: cyclopia,
proboscis, midline facial clefting, microcephaly
 Severe of pituitary/hypothalamic dysfunction (75%
especially diabetes insipidus) & disturbed body
temperature regulation
 Correlates with degree of hypothalamic non-separation
 Seizures (50%) & mental retardation
 Most severe with cortical malformations
 Dystonia & hypotonia
 Severity correlates with degree basal ganglia non-separation
Classification
 Defined by degree of frontal lobe fusion
 Sylvian angle (of Barkovich) = lines drawn tangentially
through Sylvian fissures
 Anteriorly displaced Sylvian fissures results in increased
Sylvian angle
 The larger the Sylvian angle is the more severe frontal
lobe hypoplasia is too
 3 types of HPE based on criteria (lobar, semilobar, and
alobar), as well as a middle interhemispheric variant,
septooptic dysplasia, and single central incisor
Alobar Holoprosencephaly
 “Pancake” or “horseshoe” brain
 Monoventricle
 Large dorsal cyst
 Fused diencephalon
 Basal ganglia & thalami may form gray matter fusion
mass
 No interhemispheric fissure
 No olfactory nerves
Alobar HPE: note fused thalamic & hemispheres,
monoventricle, absent interhemispheric fissure
and venous sinsues, & azygous ACA.
Fetal MRI shows alobar HPE.
MR T1 images in alobar HPE.
Diagnosis of HPE by Ultrasound
 Diagnosis of HPE by ultrasound can be made as early
as 9 weeks gestational age.
 Development of forebrain can be delineated in detail
with ultrasound from 7 weeks on.
 Alobar HPE may be detectable as early as the end of
week 7
 Non-visualization of the butterfly sign is very helpful
in diagnosis
Semilobar Holoprosencephaly
 Partial occipital/temporal horns
 Moderate sized dorsal cyst
 Fused diencephalon
 Partial fusion of basal ganglia > thalami
 Interhemipheric fissure present posteriorly
 Absent of hypoplastic olfactory tracts and bulbs
 Corpus callosum is rudimentary
CT in semilobar HPE.
MRI in semilobar HPE.
Lobar Holoprosencephaly
 Formed lateral ventricles
 Small or no dorsal cyst
 Fused diencephalon and/or fornices
 +/- partial fusion of basal ganglia > thalami
 Interhemispheric fissure nearly normal
 Small or normal olfactory nerves
MRI in lobar HPE.
Middle Interhemispheric Variant
 Sylvian fissures connect across midline over vertex (86%)
 Interhemispheric fusion of posterior frontal/parietal lobes,
with normal separation of anterior frontal/occipital lobes
 Non-cleavage of thalami > basal ganglia
 Heterotopias and cortical dysplasias common (86%)
 Thought to reflect abnormal induction of embryonic roof
plate
 Classic HPE = abnormal induction of embryonic floor plate
 May explain absence of craniofacial malformations
 Spasticity, hypotonia, seizures, developmental delay
MRI in midline intehemispheris variant of HPE.
References
 Sepulveda Waldo, Dezerega Victor, Be Cecilia. First-Trimester
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Sonographic Diagnosis of Holoprosencephaly. Journal of Ultrasound
in Medicine 23: 761-765.
Hahn Jin, Barnes Patrick. Neuroimaging Advances in
Holoprosencephaly: Refining the Spectrum of the Midline
Malformation. American Journal of Medical Genetics 154C: 120-132.
Blaas H., Eriksson A., Salvesen K., et al. Brains and faces in
holoprosencephaly: pre- and postnatal description in 30 cases.
Ultrasound Obstet Gynecol 2002; 19: 24-38.
Takanashi Jun-ichi, Barkovich A. James, Clegg Nancy, Delgado
Mauricio. Middle Interhemispheric Bariant of Holoprosencephaly
Associated with Diffuse Polymicrogyria. AJNR 2003; 24: 394-397.
Simon Erin, Hevner Robert, Pinter Joseph, et al. The Middle
Interhemispheric Variant of Holoprosencephaly. AJNR 2002; 23: 151155.