Radiography
Findings
Craniofacial defects associated with holoprosencephaly that may be detected on plain radiographs include a single, fused orbit; orbital hypotelorism; abnormal nasal bone formation; facial clefts; and a single, midline, central incisor.
Degree of Confidence
Changes apparent on plain radiography are nonspecific and insufficient to make the diagnosis of holoprosencephaly.
False Positives/Negatives
Not all individuals with holoprosencephaly have craniofacial abnormalities that are detectable on plain radiography. However, holoprosencephaly is in the differential diagnosis whenever these associated anomalies are found.
Computed Tomography
Findings
On CT scan images, alobar holoprosencephaly results in a horseshoe-shaped monoventricle, an absent interhemispheric fissure, fused thalami, an absent falx, agenesis of the corpus callosum, an absent septum pellucidum, and absent olfactory bulbs.
Semilobar holoprosencephaly is characterized by partial ventricular differentiation but with a single ventricular cavity, a partial interhemispheric fissure and falx (posterior-ventral axis), partial or incomplete formation of the corpus callosum, and a variable degree of thalamic fusion. The olfactory bulbs are often absent. The abnormality is more severe anteriorly, with partial cleavage and lateral differentiation occurring posteriorly. In these individuals, the posterior portion of the corpus callosum is present, and the more anterior portion, where failure of cleavage has occurred, is absent.
Lobar holoprosencephaly occurs with partial fusion of the frontal lobe with an otherwise normally formed interhemispheric fissure, lateral ventricular formation, variable and incomplete absence of the anterior corpus callosum and/or septum pellucidum, and separate thalami. The olfactory tracts are present.
The middle interhemispheric fusion variant appears as incomplete cleavage of the posterior frontal and parietal lobes and, often, incomplete cleavage of the basal ganglia and thalami. The body of the corpus callosum is absent in the area where cleavage has failed to occur.
Degree of Confidence
CT scans can establish a diagnosis of holoprosencephaly by providing images of the brain anatomy. CT scanning is best suited for imaging the bony structure of the skull.
False Positives/Negatives
CT scanning provides less detail of the brain parenchyma than MRI and does not provide good images of the posterior fossa and brainstem. Therefore, some cases of mild holoprosencephaly and associated CNS anomalies can be missed on CT scans.
In addition, CT scanning exposes the patient to ionizing radiation and is therefore relatively contraindicated in the prenatal diagnosis.
Magnetic Resonance Imaging
Findings
Cranial MRI is the diagnostic imaging modality of choice for cases of holoprosencephaly.
Alobar holoprosencephaly results in a horseshoe-shaped monoventricle, an absent interhemispheric fissure, fused thalami, an absent falx, agenesis of the corpus callosum, an absent septum pellucidum, absent olfactory bulbs, abnormal cerebral cortex, and migration anomalies.
Semilobar holoprosencephaly is characterized by partial ventricular differentiation but with a single ventricular cavity, a partial interhemispheric fissure and falx (posterior-ventral axis), partial or incomplete formation of the anterior corpus callosum, and a variable degree of thalamic fusion. The olfactory bulbs are often absent.
Lobar holoprosencephaly occurs with partial fusion of the frontal lobe with an otherwise normally formed interhemispheric fissure, lateral ventricular formation, variable and incomplete absence of the anterior corpus callosum and/or septum pellucidum, and separate thalami. The olfactory tracts are present.
The middle interhemispheric fusion variant appears as incomplete cleavage of the posterior frontal and parietal lobes and incomplete cleavage of the basal ganglia and thalami. The body of the corpus callosum is absent, coincident with the site of failure of cerebral separation.
Degree of Confidence
Cranial MRI is the diagnostic imaging modality of choice.
False Positives/Negatives
Fetal MRI may yield both false-positive and false-negative results if the study is not performed according to established protocols and if the images are not interpreted by an experienced individual. Fetal activity can significantly degrade the images and may need to be circumvented by repeated sequences. Single-shot fast spin-echo (SS-FSE) MRI techniques can also often circumvent this problem.
Ultrasonography
Findings
At prenatal ultrasonography, primary CNS findings include the following: (1) single, sickle-shaped or horseshoe monoventricle; (2) absent midline echo due to the absence of an interhemispheric fissure, falx, corpus callosum, and septum pellucidum; (3) thin cortical rim; (4) single, fused thalamus; (5) microcephaly; and (6) ventriculomegaly/hydrocephalus.
Associated craniofacial ultrasonographic findings include the following: (1) ocular hypotelorism or cyclopia, (2) proboscis or abnormal nasal bone formation, and (3) cleft lip and/or palate (midline or bilateral).
Postnatally, alobar holoprosencephaly shows a single ventricle, fused thalami, and a thin, usually poorly differentiated cortical mantle. A dorsal cyst or ventricular remnant may also be detected.
Semilobar holoprosencephaly is detected by identifying the partial cleavage of the occipital horns and the presence of a posterior falx and a posterior portion of the corpus callosum. Anteriorly, there is typically fusion of the ventricles and of the hemispheres, with concomitant absence of the corpus callosum and of the septum pellucidum.
Lobar holoprosencephaly is a continuum. In some patients, the ultrasonographic images show fusion of the anterior horns and of portions of the frontal lobes. The mildest forms of lobar holoprosencephaly may be manifested only by absence of the septum pellucidum.
Sonograms of the middle interhemispheric fusion variant demonstrate normal cleavage anteriorly and posteriorly, with fusion of the hemispheres and absence of body of the corpus callosum in the posterior, frontal, and parietal regions.
Degree of Confidence
Reportedly, cases of alobar holoprosencephaly have been detected as early as 9-14 weeks' gestation (and often detected at 18-20 weeks on routine anatomic scans), semilobar holoprosencephaly has been detected by 13-20 weeks' gestation, and lobar holoprosencephaly has been detected by 21 weeks' gestation with the use of transvaginal ultrasonography. Conventional transabdominal ultrasonography cannot achieve this degree of early detection.
Fetal MRI should be considered to confirm and further classify cases of holoprosencephaly.
False Positives/Negatives
Prenatal ultrasonography is not a reliable method of diagnosing mild forms of holoprosencephaly, such as lobar holoprosencephaly, because of its high false-negative rate. In addition, prenatal ultrasonography often cannot distinguish between alobar holoprosencephaly and semilobar holoprosencephaly. Transabdominal ultrasonographic diagnosis of holoprosencephaly before 16 weeks of gestation is difficult.
A false-positive diagnosis of holoprosencephaly has been reported in cases of hydrocephalus, hydranencephaly, arachnoid or porencephalic cysts, Dandy-Walker malformations with ventriculomegaly, septo-optic dysplasia, and other CNS malformations.
Nuclear Imaging
Findings
Nuclear medicine studies are not helpful in establishing a diagnosis of holoprosencephaly.
Angiography
Findings
Angiography is not indicated because it is unnecessary in establishing a diagnosis of holoprosencephaly. However, in the past, an azygous anterior cerebral artery running over the cerebral surface has been documented by angiography, in cases of alobar and semilobar holoprosencephaly, to correlate somewhat with the degree of holoprosencephaly.
More on Holoprosencephaly |
| Overview: Holoprosencephaly |
 Imaging: Holoprosencephaly |
| Follow-up: Holoprosencephaly |
| Multimedia: Holoprosencephaly |
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References
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Muenke M, Beachy PA. Holoprosencephaly. In: Scriver CR, Beaudet AL, Sly WS, et al, eds. The Metabolic & Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw-Hill; 2001:6203-30.
Leoncini E, Baranello G, Orioli IM, et al. Frequency of holoprosencephaly in the International Clearinghouse Birth Defects Surveillance Systems: Searching for population variations. Birth Defects Res A Clin Mol Teratol. Jun 19 2008;epub ahead of print. [Medline].
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The Carter Centers for Brain Research in Holoprosencephaly and Related Malformations. Information about holoprosencephaly. Available at http://hpe.stanford.edu/about/. Accessed August 1, 2008.
Lewis AJ, Simon EM, Barkovich AJ, et al. Middle interhemispheric variant of holoprosencephaly: a distinct cliniconeuroradiologic subtype. Neurology. Dec 24 2002;59(12):1860-5. [Medline].
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McGahan JP, Nyberg DA, Mack LA. Sonography of facial features of alobar and semilobar holoprosencephaly. AJR Am J Roentgenol. Jan 1990;154(1):143-8. [Medline]. [Full Text].
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Keller K, McCune H, Williams C, Muenke M. Lobar holoprosencephaly in an infant born to a mother with classic phenylketonuria. Am J Med Genet. Nov 13 2000;95(2):187-8. [Medline].
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Roessler E, Du YZ, Mullor JL, Casas E, et al. Loss-of-function mutations in the human GLI2 gene are associated with pituitary anomalies and holoprosencephaly-like features. Proc Natl Acad Sci U S A. Nov 11 2003;100(23):13424-9. [Medline]. [Full Text].
Warr N, Powles-Glover N, Chappell A, et al. Zic2-associated holoprosencephaly is caused by a transient defect in the organiser region during gastrulation. Hum Mol Genet. Jul 9 2008;epub ahead of print. [Medline].
Further Reading
NINDS Holoprosencephaly Information Page.
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD
Information About Holoprosencephaly.
Carter Centers for Research in Holoprosencephaly.Texas Scottish Rite Hospital P.O. Box 190567, 2222 Welborn Street, Dallas, TX
Keywords
holoprosencephaly, HPE, alobar holoprosencephaly, alobar HPE, lobar holoprosencephaly, lobar HPE, semilobar holoprosencephaly, semilobar HPE, arrhinencephaly, cebocephaly, cyclopia, ethmocephaly, holotelencephaly, Shh gene, Sonic Hedgehog protein, ZIC2, SIX3, TGIF, monoventricle, fused cerebral hemispheres, middle interhemispheric fusion variant, MIHF
