Midbrain and hindbrain malformations: advances in clinical diagnosis, imaging, and genetics

Abstract

Historically, the midbrain and hindbrain have been considered of secondary importance to the cerebrum, which has typically been acknowledged as the most important part of the brain. In the past, radiologists and pathologists did not regularly examine these structures-also known as the brainstem and cerebellum-because they are small and difficult to remove without damage. With recent developments in neuroimaging, neuropathology, and neurogenetics, many developmental disorders of the midbrain and hindbrain have emerged as causes of neurodevelopmental dysfunction. These research advances may change the way in which we treat these patients in the future and will enhance the clinical acumen of the practising neurologist and thereby improve the diagnosis and treatment of these patients.

Figure 1. MBHB development and genes associated with human MBHB malformations

The diagrams depict representative stages of mouse MBHB development, the model in which MBHB development is best understood. The upper diagrams depict views from the dorsal aspect at E9.5, E12.5 and E18.5 (days after conception in the mouse embryo). Dotted lines in the upper diagrams indicate the position of the axial (A) or sagittal (B and C) cross sections depicted in the lower diagrams. (A) The lower figure represents an axial cut through most rostral level of the hindbrain. HOXA1 is involved in Anterior/Posterior (A/P) patterning of the MBHB, while rhombencephalosynapsis may be due to defects in Dorsal/Ventral (D/V) patterning at the most dorsal and rostral aspect of the hindbrain (red area), where the cerebellar vermis is formed. (B) The upper diagram shows the location of early vermis formation at the most dorsal and anterior portion of the hindbrain (red circle). Early vermis formation may require the genes involved in Joubert/Meckel syndromes. Lower image (sagittal view) shows PTF1A expressed in the cerebellar ventricular zone is required for GABAergic Purkinje cell precursor fate, FOXC1 is required for induction between mesenchyme and rhombic lip, and the RELN pathway, O-glycosylation genes, and tubulins are likely required for migration of precursors out of the rhombic lip and ventricular zone. (C) By E18.5, the mouse cerebellar hemispheres (blue in upper figure) and vermis (yellow in upper figure) have partially formed. The midline sagittal (lower) diagram depicts early foliation and cortical lamination. Multiple pathways are likely involved in proliferation, migration, and survival of neuronal precursors and other cell types. ROBO3, Joubert/Meckel and tubulin genes are required for axon pathfinding to establish connections with cerebellar and brainstem nuclei. Fore=Forebrain, Mid=Midbrain, Hind=Hindbrain

Figure 2. Normal brain MRI images

(A) Sagittal image demonstrates patent aqueduct, normal tectum, normal sized posterior fossa, vermis and pons (P), straight brainstem with flat dorsal surface (dotted line), appropriately positioned fastigium (arrowhead) just below the mid-point of the ventral pons, primary (red arrow) and pre-pyramidal (white arrow) fissures dividing vermis into 3 segments. Yellow arrows and numbers give approximate proportions of brain stem. (B) Coronal image demonstrating normal-sized cerebellar hemispheres and vermis (red arrowhead) with folia radiating toward the deep cerebellar nuclei; Note primary fissure (red arrow). (C and C′) Coronal images demonstrating superior (SCP), middle (MCP) and inferior (ICP) cerebellar peduncles. (D-D″) Axial images demonstrating SCP, MCP and ICP; note the normal-sized cerebellar hemispheres and vermis.

Figure 3. Sagittal views of MBHB malformations

(A) Normal sagittal image for comparison. (B) Dandy-Walker malformation (unknown cause) with hypoplastic, rotated vermis and marked enlargement of 4^th ventricle and posterior fossa. (C) Cerebellar hypoplasia in a patient with biallelic RELN mutations, demonstrating hypoplastic brainstem and characteristic absent folia of the vermis; note the normal tectum. (D) Tubulinopathy (TUBA1A mutation) with brainstem hypoplasia, vermis hypoplasia, lissencephaly and microcephaly; note the large, dysplastic tectum. (E) Rhombencephalosynapsis (unknown cause) with hemisphere-like vermis morphology (the three segments described in Fig 2A are not seen); note the normal size and configuration of the pons and vermis. (F) Pontocerebellar hypoplasia (homozygous TSEN54 mutation) with hypoplastic brainstem and vermis (which is less affected than hemispheres), note the normal tectum. (G) Pontocerebellar hypoplasia in a patient with congenital diabetes; note the extremely small vermis and flat pons with preserved tectum. (H) CASK-related PCH; note that the pons is not severely affected in this patient. (I) Pontine tegmental cap dysplasia (unknown cause) with ventral pons hypoplasia and an ectopic “cap” of white matter on the dorsal pons (arrowhead); the vermis is mildly hypoplastic with prominent folia. (J) Congenital disorders of glycosylation Type 1a due to biallelic PMM2 mutations. (K) TCTN2-related Joubert syndrome with vermis hypoplasia (obscured by hemispheres in this image), horizontal superior cerebellar peduncles, large dysplastic tectum and heterotopia at the dorsal cervicomedullary junction (arrowhead). With kind permission from Springer Science and Business Media: Juric-Sekhar G, Adkins J, Doherty D, Hevner RF. Joubert syndrome: brain and spinal cord malformations in genotyped cases and implications for neurodevelopmental functions of primary cilia. Acta Neuropathol 2012; 123: 695–709. (L) Muscle-eye-brain disease (MEB) due to POMTGN1 mutations; note the markedly hypoplastic and dysplastic brainstem, cerebellar cysts, abnormal tectum and hydrocephalus.

Figure 4. Other imaging features of MBHB malformations

(A) Incomplete lissencephaly (pachygyria) in a patient with biallelic RELN mutations. (B) Unilateral cerebellar hemisphere hypoplasia with milder vermis hypoplasia in a patient with PHACE syndrome (unknown cause). (C) Deficient vermis and fused cerebellar white matter tracts in a patient with rhombencephalosynapsis (unknown cause). (D) Inferior cerebellar hemisphere dysplasia in a patient with Chudley-McCullough syndrome (CMS) due to a homozygous GPSM2 mutation. (E) Cerebellar hypoplasia with relatively preserved vermis in a patient with PCH due to biallelic TSEN54 mutations. (F) Cerebellar hypoplasia with proportionally affected hemispheres and vermis in a patient with PCH due to a CASK mutation. (G) Molar tooth sign in a patient with Joubert syndrome due to a homozygous TMEM216 mutation. (H) Cobblestone cortical malformation and abnormal white matter signal in a patient with Muscle-eye-brain disease due to POMTGN1 mutations. (I) Dysplastic pons in a patient with HGPPS due to biallelic ROBO3 mutations; compare to Figure 2D.