Case of the Week

Background:

• Holoprosencephaly (HPE) is a spectrum of disorders resulting from abnormal formation of the rostral end of the neural tube.
• The middle interhemispheric variant (MIHV), also known as syntelencephaly, is characterized by abnormal nonseparation of the posterior frontal and parietal lobes.
• Unlike other forms of HPE that result from abnormal induction of the embryonic floor plate of the neural tube, MIHV results from abnormal induction of the roof plate.
• Similar to other forms of HPE, mutations of the ZIC2 gene, located on chromosome 13, have been implicated in the pathogenesis of MIHV.

Clinical Presentation:

• Patients may present with a variety of deficits, including hypotonia and oromotor deficits affecting speech and feeding, with symptom severity driven by the degree of involvement of the motor cortex.
• Symptoms are usually less severe in MIHV than in the alobar, semilobar, or lobar forms of HPE.

Key Diagnostic Features:

• MIHV is distinct from the other forms of HPE in that there is nonseparation of the posterior frontal and parietal lobes with preserved separation of the anterior frontal and occipital lobes.
• The Sylvian fissure has a unique morphology in MIHV, taking a vertical orientation. Together, the Sylvian fissures create a characteristic transverse fissure extending to the vertex, which is not particularly striking in this case.
• There is aplasia or severe hypoplasia of the body of the corpus callosum with relative preservation of the rostrum, genu, and splenium.
• The cerebral falx is deficient in the middle interhemispheric region and the septum pellucidum is absent.
• There may be hypoplasia of the frontal horns of the lateral ventricles, as seen in this case.
• Thalamic fusion may be present, and when present correlates with the finding of a dorsal cyst.
• Gray matter heterotopia and cortical dysplasias are commonly associated findings.

Differential Diagnoses:

• Alobar HPE: This is the most severe form of HPE and is characterized by diffuse nonseparation of the cerebral hemispheres, fusion of the thalami, absent corpus callosum, and a monoventricle communicating with a dorsal cyst. Corresponding midline facial features are common and may include a proboscis, cyclopia, hypotelorism, or a mononostril.
• Semilobar HPE: In this intermediate form of HPE, there is fusion of the frontal lobes and thalami with separation of the parietal and occipital lobes. The rostrum, genu, and body of the corpus callosum are absent with preservation of the splenium. The frontal horns of the lateral ventricles are absent. Corresponding facial features are more mild or absent.
• Lobar HPE: Less severe than the semilobar form, lobar HPE is characterized by normal separation of the cerebral hemispheres with the exception of nonseparation of the basal portions of the frontal lobes and fusion of the fornices and frontal horns of the lateral ventricles. The rostrum and genu of the corpus callosum are absent with preservation of the body and splenium. The thalami are usually not fused.
• Septo-optic dysplasia (SOD): Considered by many to be the mildest developmental abnormality on the HPE spectrum, SOD is characterized by an absent septum pellucidum and varying degrees of optic nerve hypoplasia with preserved separation of the cerebral hemispheres and thalami. There is a strong association with schizencephaly as well as with cortical dysplasias and pituitary abnormalities.

Treatment:

• Management is supportive.
• Accurate imaging diagnosis aids with prognostic and genetic counseling.