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Case Reports
. 2011 Apr;121(4):545-54.
doi: 10.1007/s00401-010-0748-0. Epub 2010 Sep 21.

Neuronal migration disorders in microcephalic osteodysplastic primordial dwarfism type I/III

Gordana Juric-Sekhar  1 , Raj P Kapur, Ian A Glass, Mitzi L Murray, Shawn E Parnell, Robert F Hevner
Affiliations
Case Reports

Neuronal migration disorders in microcephalic osteodysplastic primordial dwarfism type I/III

Gordana Juric-Sekhar et al. Acta Neuropathol. 2011 Apr.

Abstract

Microcephalic osteodysplastic primordial dwarfism (MOPD) is a rare microlissencephaly syndrome, with at least two distinct phenotypic and genetic types. MOPD type II is caused by pericentrin mutations, while types I and III appear to represent a distinct entity (MOPD I/III) with variably penetrant phenotypes and unknown genetic basis. The neuropathology of MOPD I/III is little understood, especially in comparison to other forms of lissencephaly. Here, we report postmortem brain findings in an 11-month-old female infant with MOPD I/III. The cerebral cortex was diffusely pachygyric, with a right parietal porencephalic lesion. Histologically, the cortex was abnormally thick and disorganized. Distinct malformations were observed in different cerebral lobes, as characterized using layer-specific neuronal markers. Frontal cortex was severely disorganized and coated with extensive leptomeningeal glioneuronal heterotopia. Temporal cortex had a relatively normal 6-layered pattern, despite cortical thickening. Occipital cortex was variably affected. The corpus callosum was extremely hypoplastic. Brainstem and cerebellar malformations were also present, as well as old necrotic foci. Findings in this case suggest that the cortical malformation in MOPD I/III is distinct from other forms of pachygyria-lissencephaly.

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Figures

Fig. 1
Fig. 1
The patient at age 9 months. Note a sloping forehead, sparse hair and eyebrows, periorbital fullness, and small low-set ear. b, c Talipes equinovarus and rocker-bottom foot with overriding of the fourth toe by the fifth, and markedly thickened plantar creases and edema. d Spade-like hand along with brachydactyly and clinodactyly of the index finger. (Written informed consent was obtained from the patient’s mother for showing the images in this figure.)
Fig. 2
Fig. 2
Radiological findings. Flat-plate images at age 3 months showed: a Patchy sclerosis of the bones and bilateral hip dislocation. b, c Mildly slender long bones and narrow intramedullary cavities. d Fingers were bent, albeit with well-formed phalanges. e Deficient phalanges of the toes. MRI of the brain at age 9 months (f axial T1-weighted, g coronal T2-weighted) revealed diffuse bifrontal hypoplasia and lissencephaly, with temporal, parietal and occipital lobes affected to a lesser extent. The corpus callosum was not identified; the deep grey nuclei and thalamus were unremarkable. Prior hemorrhages or infarcts were noted in white matter. The large interhemispheric defect (g) seemed to communicate with the third ventricle
Fig. 3
Fig. 3
Brain at postmortem examination. a The cerebrum was asymmetric with smaller right hemisphere than the left; gyri were reduced and thick, worse frontal, with midline attachment of the frontal lobes due to leptomeningeal fusion (black arrows). b Lateral view demonstrated inferior and superior temporal gyri; porencephaly was seen in the right parietal region with a thin membrane (white arrow). c Inferior view demonstrated the simplified hemispheric surface with absent rhinal sulci; a yellowish necrotic area was found in the right midbrain tegmentum (dashed back arrow). d Sagittal sections showed a hypoplastic corpus callosum (black arrows), crossing only at the genu. e Coronal slices of the right hemisphere. The cortex was thick, measuring 0.7–0.8 cm (dashed black lines), while white matter was very thin. The hippocampus was small. The porencephalic defect was transmural (white arrow). Cystic yellow necrotic foci were seen at the grey–white interface and in deep grey nuclei (black arrows). Scale bars in a–e indicate centimeters
Fig. 4
Fig. 4
Histopathology of frontal cortex showing 3-layered lissencephaly. The layers I, II, III, and white matter (WM) are indicated on the H&E stained section. The leptomeninges demonstrated a crust of glioneuronal heterotopia (white asterisk). The superficial layer (I) of frontal cortex appeared hyperconvoluted, resembling polymicrogyria. Layer II consisted of disorganized medium- to large-sized pyramidal cells, many labeled with MAP-1B and N52 immunoreactivity. Interneurons labeled by calretinin were distributed mainly in layer II. Layer III contained small-sized neurons, many labeled with MAP-1B, as well as N52 immunoreactive axon bundles orientated radially in the cortex. The boundary between grey and white matter was blurred. (Insets show higher magnifications of boxed areas.)
Fig. 5
Fig. 5
Histopathology of temporal cortex. H&E staining showed the 6-layered pachygyric cortex designated by Roman numerals I to VI, and the white matter (WM). Note leptomeningeal glioneuronal heterotopia (white asterisk). Layer V contained large pyramidal neurons labeled with MAP-1B and N52. Layer VI contained N52-immunopositive, radially oriented axon bundles (lower inset). Calretinin immunolabeled interneurons were seen mainly in layer II. The boundary between grey and white matter was not well defined. (Insets show higher magnifications of boxed areas.)
Fig. 6
Fig. 6
Histopathology of occipital cortex. H&E demonstrated neuronal disorganization with primitive 3-layered lissencephaly, and a poorly defined boundary with white matter (WM). MAP-1B and N52 immunopositive pyramidal cells were found in layer II. Interneurons labeled by calretinin were mainly distributed in layer II. (Insets show higher magnifications of boxed areas.)
Fig. 7
Fig. 7
a Cerebellum, demonstrating focal loss of calbindin-immunoreactive Purkinje cells. b Heterotopic granule neurons and Purkinje cells were found in the cerebellar leptomeninges. (Inset shows higher magnification of boxed area.) c The hippocampus and dentate gyrus were hypocellular (H&E). d MAP-1B immunostaining demonstrated the inferior olives with moderately simplified convolutions. The pyramidal tract was severely hypoplastic and virtually absent
Fig. 8
Fig. 8
Schematic illustrations of the 3-layered lissencephaly of the frontal and the occipital lobes, and 6-layered pachygyric cortex of the temporal lobe, compared to normal cortex as labeled by MAP-1B, N52, and calretinin. The normal cortex has a relatively hypocellular molecular layer I (brown, yellow). Layer II contains calretinin immunolabeled neurons (red), found also in layer III along with small pyramidal neurons (blue). Layer IV contains small granular neurons (yellow), while layer V, the internal pyramidal cell layer, highlights medium-to-large MAP-1B and N52 positive pyramidal cells (grey). Layer VI is the fusiform and multiform layer (green, purple, brown), and below this is the white matter (striped white–grey). In the present case, layer I of the frontal and the occipital lobes was moderately cellular and contained various neuron types including MAP-1B, N52, and calretinin-immunopositive cells. Below this was a disorganized pyramidal cell layer highlighted by MAP-1B and N52 immunopositive cells designated layer II. Layer III was thickened and consisted of mostly small MAP-1B and N52 positive pyramidal cells, calretinin labeled cells, and other small- to medium-sized unlabeled cells. The temporal lobe had a relatively normal cytoarchitecture, although markedly thickened. The white matter was reduced in all lobes
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