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

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: 120132.
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:
151-155.