A developmental and genetic classification for midbrain-hindbrain malformations

Abstract

Advances in neuroimaging, developmental biology and molecular genetics have increased the understanding of developmental disorders affecting the midbrain and hindbrain, both as isolated anomalies and as part of larger malformation syndromes. However, the understanding of these malformations and their relationships with other malformations, within the central nervous system and in the rest of the body, remains limited. A new classification system is proposed, based wherever possible, upon embryology and genetics. Proposed categories include: (i) malformations secondary to early anteroposterior and dorsoventral patterning defects, or to misspecification of mid-hindbrain germinal zones; (ii) malformations associated with later generalized developmental disorders that significantly affect the brainstem and cerebellum (and have a pathogenesis that is at least partly understood); (iii) localized brain malformations that significantly affect the brain stem and cerebellum (pathogenesis partly or largely understood, includes local proliferation, cell specification, migration and axonal guidance); and (iv) combined hypoplasia and atrophy of putative prenatal onset degenerative disorders. Pertinent embryology is discussed and the classification is justified. This classification will prove useful for both physicians who diagnose and treat patients with these disorders and for clinical scientists who wish to understand better the perturbations of developmental processes that produce them. Importantly, both the classification and its framework remain flexible enough to be easily modified when new embryologic processes are described or new malformations discovered.

Figure 1

Mid-hindbrain embryonic development. (A) Early neural tube development—e9.5 mouse embryo stained for Lmx1b expression—a transcription factor expressed in many places of the embryo including the isthmic organizer (IsO) a signalling center at the midbrain (m) hindbrain (h) boundary adjacent to hindbrain rhombomere 1 (rh 1). The isthmic organizer secretes fibroblast growth factor (Fgf) and Wnt proteins which provide regional identity and pattern proliferation along the anterior/posterior axis. To the right is a schematic parasagittal section through the mid/hindbrain region. Arrows indicate anterior/posterior (A/P) and dorsal/ventral (D/V) axes. f = forebrain; aq = aqueduct; 4^th = fourth ventricle. (B) Distinct progenitor domains along the dorsal/ventral axis of rhombomere 1 give rise to distinct structures. A schematic diagram of a hemi-transverse section through rhombomere 1 (indicated by dashed line in A). The cerebellum is derived from the dorsal-most domain of rhombomere 1 alar plate, adjacent to the rhombic lip (rl) and dorsal roof plate (rp). The roof plate secretes bone morphogenic protein (Bmp) and Wnt proteins which pattern dorsal cell fate and proliferation. Fate mapping experiments in chick/quail chimeras have demonstrated that other alar derived structures include the superior vestibular nucleus (VeS) and principle trigeminal sensory nucleus (PrV). The locus coerulus (lc) is also an alar plate rhombomere 1 derivative, although its progenitors migrate tangentially to settle eventually in the basal plate. The basal plate also has multiple derivatives, including the raphe nucleus (not shown), which is patterned by the influence of Shh protein secreted from the floor plate (fp). Arrows indicate dorsal/ventral (D/V) and medial lateral (M/L) axes. (C) Within the cerebellar anlage, distinct progenitors give rise to glutamtergic versus GABAergic neurons. Schematic parasagittal section through the mid/hindbrain region of a mouse e12.5 neural tube. Pontine flexure has rearranged the previously A/P oriented cerebellar anlage relative to the brainstem and developing pontine nucleus (pn). Within the developing cerebellar anlage two distinct progenitor zones form marked by distinct transcription factors, Math1 and Ptf1a. Math1 expression in the rhombic lip (rl) was induced by bone morphogenic protein signalling from the roof plate (rp) which itself is differentiating into the choroid plexus (CPe). Math1+ rhombic lip progenitor cells give rise to multiple glutamaterigic+ derivatives in a time-dependent sequence. Early progenitors feed into the rostral migratory stream (RLS). The rostral migratory stream migrates over the cerebellar anlage and gives rise to multiple brain stem precerebellar nuclei, including the pontine nuclei. Rostral migratory stream cells next give rise to glutamategic deep cerebellar nuclei which settle into the nuclear transitory zone (ntz). Math1+ rhombic lip cells also generate cerebellar granule cells (GC) which form the cerebellar external granule layer in a anterior to posterior temporal gradient. Unipolar brush cells (UBC) are the final Math1+ rhombic lip population and migrate through the cerebellar while matter. Concurrently, the ventricular zone (vz) of the cerebellar anlage expresses Ptf1a. These progenitors exit the cell cycle, migrate radially into the cerebellar anlage and give rise to all GABAergic cerebellar cells, including Purkinje cells, GABAergic DCN and interneurons including Basket and Stellate cells.

Figure 2

Defect of anteroposterior patterning. Sagittal T₁-weighted magnetic resonance image shows a short midbrain and elongated pons. Note the enlarged superior cerebellar vermis (arrows). These findings suggest alteration of caudal mesencephalon to rostral rhombencephalon, an anterior to posterior transformation, or rostral displacement of the midbrain-hindbrain boundary due to increased Gbx2 expression or reduced Otx2 expression.

Figure 3

Elongation of the medulla with shortening of the pons. Sagittal T₁-weighted image shows a long midbrain and shortened pons. The tectum is dysmorphic and the cerebellum is dysmorphic and small. These findings suggest alteration of rostral rhombencephalon to caudal mesencephalon, a posterior to anterior transformation, with caudal displacement of the midbrain-hindbrain boundary due to decreased Gbx2 expression or increased Otx2 expression.

Figure 4

Abnormality of diencephalic-mesencephalic junction. (A) Sagittal T₁-weighted image shows a thick midbrain (arrows) and a poorly-defined junction between the midbrain and the diencephalon. (B) Axial T₂-weighted image shows that the hypothalamus and midbrain appear to merge, and the third ventricle (arrows) seems to extend into the midbrain. C. Coronal fluid attenuation inversion recovery image shows the midbrain seemingly continuous with the thalami.

Figure 5

Profound cerebellar hypoplasia due to PTF1A mutation. (A) Sagittal T₁-weighted image shows an extremely small cerebellar vermis (small arrow) and small posterior fossa with low tentorium (arrows) and occipital lobes. (B) Axial T₂-weighted image shows extremely small cerebellar hemispheres (arrows).

Figure 6

Hindbrain disconnection syndrome. Sagittal T₂-weighted image shows nearly complete absence of the medulla, with only a few fibres (arrows) appearing to connect the somewhat small pons to the spinal cord. Controversy exists concerning the cause (genetic or acquired) of this syndrome.

Figure 7

Dandy–Walker malformations with multiple associated genetic/clinical disorders. All show a small cerebellum and a CSF containing structure that expands the posterior fossa; these seem to result from mutations of genes that affect both leptomeningeal and cerebellar development. Similar appearances are seen in patients with different gene mutations, while different appearances are seen in patients with mutations of the same gene. (A, B) Patients with deletion 3q24; note the markedly different severity of the hindbrain malformation. (C) Patient with deletion 6p25.3. (D) Patient with PHACES syndrome.

Figure 8

Microcephaly with disproportionate midbrain-hindbrain hypoplasia. Sagittal T₁-weighted image in a microcephalic neonate shows disproportionately small brainstem and cerebellum.

Figure 9

Cerebellar and pontine hypoplasia secondary to VLDLR mutation. Sagittal T₁-weighted image shows cerebral pachygyria and a very small, smooth cerebellum (arrows), characteristic of mutations involving the RELN pathway. The pons is always small with developmental cerebellar hypoplasia.

Figure 10

Midbrain and hindbrain malformations in mild dystroglycanopathy (muscle-eye-brain phenotype) due to POMT1 mutation. (A) Sagittal T₁-weighted image shows abnormal vermian foliation, large, abnormally rounded quadrigeminal plate (small arrows) and flattened ventral pons (large arrowhead). (B) Axial T₂-weighted image shows ventral pontine cleft (arrowhead) and small cerebellar hemispheric cortical cysts (small arrows).

Figure 11

Midbrain and hindbrain malformations in severe dystroglycanopathy (Walker-Warburg phenotype). (A). Sagittal T₁-weighted image shows massive hydrocephalus, a very small, dysplastic vermis (small arrowheads), large, round tectum (small arrows) and small, ventrally kinked pons (large arrowhead). (B) Axial T₂-weighted image shows the extremely small, dysmorphic cerebellar hemispheres and the small pons with ventral midline cleft.

Figure 12

Molar tooth malformation in patient with ataxia, developmental delay, and nephronophthisis. (A) Sagittal T₁-weighted image shows a thin isthmus (large arrows) and a small vermis (small arrows) with abnormal foliation. (B) Axial T₂-weighted image shows large, horizontal superior cerebellar peduncles (black arrowheads) and midline vermian cleft (white arrows).

Figure 13

Horizontal gaze palsy with progressive scoliosis secondary to ROBO3 mutation. Axial T₂-weighted image shows midline pontine dorsoventral cleft (arrows) caused by lack of midline crossing of axons.

Figure 14

Pontine tegmental cap dysplasia. Sagittal T₁-weighted image shows a small ventral pons and a dorsal tegmental ‘cap’ (arrow) that is characteristic of the malformation. Diffusion tensor imaging studies show that the cap is composed of highly anisotropic structures, likely axons, running transversely across the dorsal aspect of the pons.

Figure 15

Pontocerebellar hypoplasia type 1. Sagittal T₁-weighted image shows very small brain stem and cerebellum in this hypotonic, encephalopathic neonate. Note prominent cerebellar fissures (arrows), suggesting atrophy that started prenatally.

Figure 16

Unilateral cerebellar hypoplasia/dysplasia. Axial T₁-weighted image shows a small right cerebellar hemisphere with a large cleft (arrows) and abnormal folial pattern. Such lesions are often associated with prenatal cerebral and cerebellar injuries and, therefore, are classified as having putative prenatal onset.