Diencephalic-mesencephalic junction dysplasia: a novel recessive brain malformation

Abstract

We describe six cases from three unrelated consanguineous Egyptian families with a novel characteristic brain malformation at the level of the diencephalic-mesencephalic junction. Brain magnetic resonance imaging demonstrated a dysplasia of the diencephalic-mesencephalic junction with a characteristic 'butterfly'-like contour of the midbrain on axial sections. Additional imaging features included variable degrees of supratentorial ventricular dilatation and hypoplasia to complete agenesis of the corpus callosum. Diffusion tensor imaging showed diffuse hypomyelination and lack of an identifiable corticospinal tract. All patients displayed severe cognitive impairment, post-natal progressive microcephaly, axial hypotonia, spastic quadriparesis and seizures. Autistic features were noted in older cases. Talipes equinovarus, non-obstructive cardiomyopathy and persistent hyperplastic primary vitreous were additional findings in two families. One of the patients required shunting for hydrocephalus; however, this yielded no change in ventricular size suggestive of dysplasia rather than obstruction. We propose the term 'diencephalic-mesencephalic junction dysplasia' to characterize this autosomal recessive malformation.

Figure 1

Pedigree of Families DMJD-1592, DMJD-1825 and DMJD-1846. Facial images demonstrate shared features of bushy eyebrows, hairy forehead, broad prominent nasal root, long flat philtrum and V-shaped upper lip.

Figure 2

Structural brain images from each patient, showing the typical ‘butterfly’ appearance of the DMJ. Top row is aged-matched controls for comparison. All patients show some degree of ventriculomegaly and corpus callosum hypoplasia. Patient DMJD-1825-1 shows cerebellar vermis counter-clockwise rotation and hypoplasia. From left to right: Columns 1 and 2: axial CT (where available) or MRI at the level of the DMJ. Note the deep anterior midline cleft and elongated mesencephalon. Column 3: midline sagittal MRI showing corpus callosum hypoplasia. Column 4: coronal MRI showing corpus callosum hypoplasia and variable degrees of ventriculomegaly.

Figure 3

Key anatomical features of DMJD. T₁-weighted axial 1.2 mm thin sections from Patient DMJD-1592-2, demonstrating that the anterior midbrain cleft is continuous with the third ventricle. (A and B) Arrows indicate chiasmatic recess. (A) Optic track entering the midbrain. (B) Optic radiations coursing around midbrain. (C and D) Arrows indicate third ventricle extending posteriorly, producing the ‘butterfly’ sign. Arrowhead indicates inferior colliculi. (E) Arrow indicates third ventricle. Arrowhead indicates superior colliculi. (F) Arrow indicates massa intermedia (interthalamic adhesion), defining posterior limit of third ventricle.

Figure 4

Three-dimensional reconstruction of the surface projection of brainstem from affected individual Patient DMJD-1592-2 compared with an age-matched control. Notice the brainstem is foreshortened, thalamus is inferiorly displaced to the level of the mesencephalon, and the DMJ is thickened. Left: posterior view. Top right: lateral view. Bottom right: top–down view.

Figure 5

Disrupted corticospinal tract in DMJD. (A) Multiplane reconstruction with directional encoded colours from diffusion tension imaging of paediatric control, and two affected members in Family DMJD-1592 in comparison with MRI atlas of human white matter (Mori et al., 2011). Top: Axial plane in control shows corticopontine/corticospinal tracts evident in pons in blue (crosshairs), whereas neither patient has evident corticopontine/corticospinal tract. Middle: Coronal plate also shows corticopontine/corticospinal tract at crosshairs in control but absent in both patients. Bottom: Parasagittal plane also shows evident corticopontine/corticospinal tract in control, absent in patients. Crosshairs represent the relative plane of imaging for each of the images in the series for maximal registration correspondence. (B) Region of interest tractography of corticopontine/corticospinal tract fibre bundle (red) in each orientation from aged-matched control and the two affected members of Family DMJD-1592. Control shows the usual course of corticopontine/corticospinal tract, originating in the cortical motor area, lateral to the ventricle and then heading medially in the diencephalon/mesencephalon. Both patients show aberrant course of corticopontine/corticospinal tract, coursing laterally.

Figure 6

Homozygosity mapping results derived from comparison of exome sequencing of two affected individuals in Family DMJD-1592. The ∼20 000 variants from each patient were plotted as a function of heterozygosity/homozygosity at each allele for each chromosome (x-axis). Red bars represent regions of homozygosity, which reach maximum significance (height of red bar) on chromosomes 2, 5, 7, 10, 11, 16 and 20.