Middle interhemispheric variant of holoprosencephaly: A rare midline malformation.

Middle interhemispheric variant (MIH) of holoprosencephaly (HPE) or syntelencephaly is a rare variant of HPE characterized by abnormal midline union of the posterior frontal and parietal lobes with variable fusion of thalami. It varies from classic HPE in embryopathogenesis, severity of fusion of brain structures, associated craniofacial anomalies and clinical presentation. We report a case of MIH in a 5-year-old girl, who presented with severe developmental delay and discuss the features differentiating it from other more common forms of HPE.

Introduction

Holoprosencephaly (HPE) is a type of central nervous system malformation resulting from hypoplasia or aplasia of the most rostral end of the neural tube and premaxillary segment of the face. It is characterized by varying degrees of incomplete separation of the cerebral hemispheres and deep brain structures such as basal ganglia, thalamus, and hypothalamus.[1] Based on the severity of involvement, three categories have been described, namely alobar, semilobar, and lobar HPE.[2] A fourth type of HPE, namely middle interhemispheric variant (MIH) or syntelencephaly has been described, which is characterized by deficient interhemispheric fissure involving the high frontal convexity with normal interhemispheric separation of basal forebrain, anterior frontal and occipital lobes.[3]

Case Report

A 5-year-old girl presented to our institute with poor mental and motor development. She was younger of two children born to a nonconsanguineous Indian Hindu couple. Born by normal vaginal delivery at term, she had cried at birth and the neonatal period was uneventful. There was severe developmental delay noted since early infancy. There was no history of in-utero exposure to infections, drugs, or radiation. The elder sibling was a 7-year-old female child and was apparently healthy. There was no family history of brain malformations, developmental delays, facial abnormalities, or chromosomal abnormalities. On examination, the child had only partial neck control, reached for objects with immature grasp, could recognize only family members and vocalized meaningless vowel sounds. The child weighed 13.5 kg (<3rd percentile) with a head circumference of 48 cm (5–15th percentile). Dysmorphic facial features such as metopic prominence, bushy eyebrows with synophrys, broad nasal root, flat nasal bridge, telecanthus, and shallow philtrum were seen [Figure 1]. Neurological examination revealed normal cranial nerves, bilaterally symmetrical muscle bulk with increased tone in all the limbs, and generalized hyperreflexia. Rest of the systemic examination was normal.

Figure 1

Clinical photograph of the patient. (a) Frontal view shows metopic prominence, bushy eyebrows with synophrys, broad nasal root, telecanthus, and shallow philtrum, (b) Lateral view shows metopic prominence with flat nasal bridge

On magnetic resonance imaging (MRI), deficient interhemispheric fissure was observed in posterior frontal and parietal regions with failure of separation of posterior frontal and parietal lobes. The anterior and posterior parts of the interhemispheric fissure were normally formed. Sylvian fissures showed abnormal vertical orientation and were fused across midline over the vertex of brain. Genu and splenium of corpus callosum were normally formed, and the body was absent in the region of interhemispheric connection. Septum pellucidum was absent. Basal forebrain structures were normally cleaved. Brainstem and posterior fossa structures were normal [Figure 2]. The MRI findings are characteristic for MIH variant of HPE.

Figure 2

Magnetic resonance images of the patient. (a) Axial T1-weighted image shows abnormal orientation of sylvian fissures (arrows), which are connected across the midline and nonseparation of posterior frontal and parietal lobes (arrowheads), (b) Axial T2-weighted image at the level of basal ganglia shows normal separation of basal and anterior frontal lobes and occipital lobes. The basal ganglia and thalami are also well separated. The frontal horns are hypoplastic with absent septum pellucidum, (c) Sagittal T2-weighted image shows agenesis of body of corpus callosum (arrows) with normal splenium and genu, (d) Parasagittal T2-weighted image shows vertical orientation of sylvian fissure (arrows) and vertical course of middle cerebral artery (arrowhead)

Discussion

MIH variant of HPE differs from classic HPE in the embryopathogenetic mechanism. The embryonic neural tube differentiates into various regions of brain parenchyma by means of ventral and dorsal patterning, which are induced by specialized cell groups in the neural tube. Such cell groups form the floor plate in the ventral potion and roof plate in the dorsal portion of neural tube. MIH has been postulated to result from a defect in the induction of embryonic roof plate unlike the classic types of HPE, which result from a defect in the induction of embryonic floor plate.[4]

MIH is characterized by deficient interhemispheric fissure with failure of separation of posterior frontal and parietal lobes despite normal separation of anterior and posterior portions of the cerebral hemispheres. The basal ganglia structures are usually separated with variable fusion of thalami noted in 30–50% of cases. Sylvian fissures are characteristically oriented vertically and are connected across the midline over the vertex. The body of the corpus callosum is usually deficient in the region of interhemispheric nonseparation, whereas the genu and splenium are normally formed. Septum pellucidum is usually absent, and the ventricles may show hypoplastic frontal horns. Other common associations include cortical dysplasias, heterotopias, azygos cerebral artery, and a dorsal interhemispheric cyst.[5]

In contrast, semilobar and lobar types of HPE are characterized by defective separation of anterior and rostral parts of the frontal lobes with normal interhemispheric cleavage posteriorly. Variable degrees of fusion of basal ganglia are noted in both these conditions, whereas the thalami are separated in lobar and variably fused in semilobar type. In both these entities, the splenium is normally formed, and the rostrum and genu are absent.

The incidence of craniofacial anomalies is less severe and less frequent in MIH, when compared with the classic types of HPE.[3] Spasticity and seizures are the most common clinical findings seen in the affected children. Endocrinopathies and choreoathetosis, which are commonly observed in other forms of HPE are relatively rare in syntelencephaly due to lack of involvement of basal forebrain structures.

Despite these differences in the clinical presentation and imaging findings, MIH variant shares a common denominator with the classic forms of HPE in that there is nonseparation of a part of the supra-tentorial brain into two separate hemispheres.[67] Mutations involving the ZIC2 gene, located on human chromosome 13q32, has been postulated in the pathogenesis of HPE and syntelencephaly. It is expressed in the dorsal and ventral midline regions of the telencephalon unlike other genes identified in HPE, which are expressed predominantly in the ventral regions. In a study of 509 individuals with various types of HPE, mutations of the ZIC2 gene was observed in 16 cases. Fifteen of them had alobar, semilobar, or lobar HPE; and in the remaining one who had the MIH variant, a comparatively mild mutation of the ZIC2 gene (in-frame deletion of 12 amino acids) was observed.[8] It was suggested that the level of function of the protein determined the severity of HPE ranging from alobar to MIH variant, which in turn was dependent on the severity of mutation of the gene.

Conclusion

The MIH variant of HPE or syntelencephaly has characteristic imaging findings and radiologists are often the first to diagnose this condition. Familiarity with these findings can help in early diagnosis and prognostication of the affected children.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.