Neuroimaging Advances Unravel Complex Fetal and Perinatal Midbrain and Hindbrain Malformations

In a pictorial review published in Pediatric Radiology, researchers demonstrated that comprehensive fetal and perinatal neuroimaging is critical for diagnosing and differentiating midbrain and hindbrain malformations, a heterogeneous group of congenital central nervous system disorders characterized by overlapping clinical presentations and imaging features. Prenatal detection of these conditions plays an essential role in optimizing perinatal management, guiding genetic counseling, and establishing accurate prognostication, particularly because individual outcomes vary dramatically from favorable survival to severe lethality. Although ultrasound serves as the primary screening tool for fetal brain anomalies, its diagnostic sensitivity can be substantially constrained by maternal body habitus, fetal positioning, and the intricate anatomical architecture of the hindbrain. Consequently, fetal magnetic resonance imaging functions as an indispensable diagnostic adjunct whenever sonographic examinations yield inconclusive findings or when high-resolution anatomical evaluation of posterior fossa structures is required. To navigate these complex diagnostic challenges, the authors evaluated these conditions through a comprehensive classification framework originally established by Barkovich and colleagues, which categorizes midbrain and hindbrain anomalies based on embryological development, genetic etiology, and the molecular biology of brain patterning across four primary categories.

The first major category defined under this embryological system encompasses malformations resulting from early anteroposterior and dorsoventral patterning defects or misspecification of the mid-hindbrain germinal zones, prominently illustrated by diencephalic-mesencephalic junction dysplasia. This rare congenital neural tube anteroposterior patterning defect involves partial or complete fusion of the midbrain with diencephalic structures and presents clinically with severe neurodevelopmental impairment. The condition exhibits genetic heterogeneity, with reported mutations in PCDH12, GSX2, L1CAM, and VRK1, which are postulated to disrupt the establishment and maintenance of structural and molecular boundaries at the junction, leading to premature neuronal differentiation and migration. Neuroimaging categorizes diencephalic-mesencephalic junction dysplasia into three subtypes based on structural severity: Type A displays mesencephalic-hypothalamic fusion and a pathognomonic deep midbrain cleft communicating directly with the third ventricle, recognized on axial magnetic resonance imaging as the butterfly sign, accompanied by profound hypothalamic dysfunction, severe developmental delay, motor incoordination, epilepsy, and axial hypotonia with variable spasticity. Type B represents the most common variant, characterized by incomplete cleavage between the thalamus and midbrain, a shallow midline cleft yielding an incomplete butterfly configuration, pontine and vermian hypoplasia, and a comparatively milder phenotype that can present into adulthood. Type C reflects complete or near-complete fusion across the midbrain, thalamus, and hypothalamus, posing differential diagnostic considerations with rhombencephalosynapsis, L1CAM-related disorders, and Walker-Warburg syndrome.

Also classified within this primary group of early patterning disturbances are Möbius sequence and rhombencephalosynapsis. Its multifactorial etiology encompasses de novo mutations in PLXD1 and REV3L, chromosomal abnormalities at loci 3q21-22 and 10q, vascular disruption during embryonic development, teratogenic exposures, and uterine abnormalities, yielding clinical manifestations such as facial paralysis, developmental delay, feeding difficulties, micrognathia, microstomia, cleft palate, dental anomalies, and limb malformations including clubfoot and syndactyly. On neuroimaging, Möbius sequence exhibits hypoplastic facial colliculi with fourth ventricular floor flattening, pontine hypoplasia, tectal beaking, shallow interpeduncular cisterns, basal ganglia fusion, and ventriculomegaly. In contrast, rhombencephalosynapsis represents a dorsoventral patterning defect characterized by the absence of the cerebellar vermis accompanied by dorsal fusion of the cerebellar hemispheres, dentate nuclei, and superior cerebellar peduncles, presenting with horizontal foliation, aqueduct stenosis, and characteristic figure-of-eight head-shaking stereotypy. Rhombencephalosynapsis serves as a hallmark of Gómez-López-Hernández syndrome alongside parietal scalp alopecia, brachycephaly, and craniofacial dysmorphism, while also occurring in association with VACTERL anomalies.

The second category covers anomalies associated with later generalized developmental disorders affecting the brainstem and cerebellum, including microcephaly with disproportionate cerebellar and brainstem hypoplasia syndrome. This rare X-linked condition predominantly affects females and is most frequently caused by mutations in the CASK gene located at Xp11.4, which encodes proteins critical for neural development and synaptic function. The syndrome exhibits a broad phenotypic spectrum ranging from milder hemizygous missense variants marked by congenital nystagmus and moderate intellectual disability to severe heterozygous loss-of-function variants characterized by microcephaly, myoclonic seizures, and severe intellectual disability.

Within this same division of generalized developmental disorders, Walker-Warburg syndrome and Joubert syndrome–related disorders demonstrate severe hindbrain malformations linked to defined molecular pathways. Walker-Warburg syndrome is a universally lethal autosomal recessive congenital muscular dystrophy with an incidence of 1.2 per 100,000 live births and a median survival of nine months, caused by loss-of-function mutations across genes including POMT1, POMT2, FKTN, and ISPD that disrupt the glycosylation of α-dystroglycan and decouple the extracellular matrix from the cytoskeleton. This failure impairs sarcolemmal integrity and neuronal migration, generating neuroimaging hallmarks that include type II cobblestone lissencephaly, diffuse white matter abnormalities, midline dysgenesis, ventriculomegaly, cerebellar microcysts, and pontocerebellar hypoplasia featuring a characteristic Z-shaped brainstem kinking at the mesencephalic-pontine junction. Its pathognomonic imaging hallmark is the molar tooth sign, reflecting elongated, thickened, non-decussating superior cerebellar peduncles, vermian hypoplasia, and an abnormally deep interpeduncular fossa.

The third major category encompasses localized brain malformations preferentially affecting specific levels of the brainstem and cerebellum, exemplified by horizontal gaze palsy with progressive scoliosis. This rare autosomal recessive condition is caused by biallelic mutations in the ROBO3 gene at 11q23-25, which encodes a transmembrane axon-guidance receptor governing neuronal migration, axonal growth, and the decussation of brainstem and spinal cord pathways. Affected individuals present with congenital absence of conjugate horizontal eye movements, horizontal nystagmus, convergence anomalies, and progressive early-onset scoliosis, while vertical gaze remains preserved. High-resolution magnetic resonance imaging demonstrates a split pons sign characterized by a hypoplastic pons with reduced anteroposterior dimensions, a dorsal midline pontine cleft creating tenting of the fourth ventricular floor, bilateral absence of facial colliculi, and a butterfly-shaped medulla oblongata with prominent inferior olivary nuclei. Advanced diffusion tensor imaging with tractography provides key physiological insight, demonstrating uncrossed corticospinal tracts and uncrossed dorsal column-medial lemniscus pathways, alongside absent superior cerebellar peduncle decussation despite preserved callosal connectivity.

Localized malformations also include distinct dorsal protuberances classified as pontine tegmental cap dysplasia and medullary tegmental cap dysplasia, both hypothesized to arise from abnormal axonal guidance and impaired neuronal migration during embryogenesis. Pontine tegmental cap dysplasia is a rare, nonprogressive anomaly characterized by ventral pontine hypoplasia and a prominent vaulted dorsal tegmental cap protruding into the fourth ventricle, accompanied by middle cerebellar peduncle hypoplasia, absent inferior olivary prominence, and absence of transverse pontine fibers. Clinically, it manifests primarily as cranial nerve palsies predominantly involving cranial nerves VII and VIII, leading to facial paralysis, feeding difficulties, and bilateral sensorineural hearing loss associated with internal auditory canal hypoplasia, while diffusion tensor imaging demonstrates ectopic transverse fiber bundles within the dorsal pontine cap that lack connections to middle cerebellar peduncles. Similarly, medullary tegmental cap dysplasia presents as a dorsal medullary protuberance or gray matter cap of variable dimensions, which has been identified in association with Joubert syndrome–related disorders and fibrodysplasia ossificans progressiva, causing variable cranial nerve deficits including abnormal ocular motility, dysarthria, and hearing impairment.

The fourth category of the Barkovich classification addresses combined hypoplasia and atrophy resulting from putative prenatal-onset degenerative disorders, represented by pontocerebellar hypoplasia and cerebellar hemisphere hypoplasia. Pontocerebellar hypoplasia comprises a heterogeneous group of predominantly autosomal recessive disorders linked to mutations in more than twenty genes, including subunits of the tRNA splicing endonuclease complex and CLP1, leading to progressive microcephaly, neocortical atrophy, severe global developmental delay, chorea, and seizures, with magnetic resonance imaging demonstrating marked pontocerebellar hypoplasia and a dragonfly cerebellar configuration resulting from relative vermian preservation. In parallel, cerebellar hemisphere hypoplasia involves unilateral or bilateral underdevelopment of the cerebellar hemispheres arising from prenatal vascular disruption, intrauterine hemorrhage, infection, teratogenic exposure, or genetic syndromes involving PDGFRB signaling. The authors concluded that advances in fetal and postnatal neuroimaging over the past two decades have substantially improved the recognition of these complex developmental anomalies, demonstrating that precise magnetic resonance evaluation combined with expanding genetic knowledge provides essential guidance for clinical prognostication, parental counseling, and perinatal care.

Subject of Research: Fetal and perinatal neuroimaging of midbrain and hindbrain developmental malformations

Article Title: Fetal and perinatal neuroimaging of midbrain and hindbrain malformations

Article References: Juang, E. K., Clarke, J. E., Hoang, A. T., Goncalves, L. F., Jaju, A. I., & Cornejo, P. (2026). Fetal and perinatal neuroimaging of midbrain and hindbrain malformations. Pediatric Radiology. https://doi.org/10.1007/s00247-026-06817-6

Image Credits: AI Generated

DOI: 10.1007/s00247-026-06817-6

Keywords: pediatric neuroimaging, fetal MRI, hindbrain malformations, midbrain development, Barkovich classification, prenatal diagnosis, pontocerebellar hypoplasia, Joubert syndrome, Fetal, perinatal, neuroimaging, midbrain