Accepted Manuscript

Prenatal diagnosis of brainstem anomalies

Karina Krajden Haratz, Tally Lerman-Sagie

PII: S1090-3798(18)30229-0
DOI: 10.1016/j.ejpn.2018.06.011
Reference: YEJPN 2448

To appear in: European Journal of Paediatric Neurology

Received Date: 13 May 2018

Revised Date: 27 June 2018
Accepted Date: 28 June 2018

Please cite this article as: Haratz KK, Lerman-Sagie T, Prenatal diagnosis of brainstem anomalies,
European Journal of Paediatric Neurology (2018), doi: 10.1016/j.ejpn.2018.06.011.

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 ACCEPTED MANUSCRIPT
Prenatal diagnosis of brainstem anomalies

Karina Krajden Haratz1,2,3, Tally Lerman-Sagie1,3,4

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1. Fetal Neurology Clinic, Ultrasound in Ob-Gyn Unit, Wolfson Medical

Center, Holon, Israel

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2. Lis Maternity Hospital, Tel Aviv Medical Center, Tel Aviv, Israel

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3. Sackler School of Medicine, Tel Aviv University

4. Pediatric Neurology Unit, Wolfson Medical Center, Holon, Israel

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Correspondence:
Karina Krajden Haratz
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Fetal Neurology Clinic,

Wolfson Medical Center
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Halohamim 52, Holon

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Israel
k.neurofetal@gmail.com
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Abstract

Prenatal diagnosis of brainstem anomalies is important due to the usually

associated neurodevelopmental impairment and genetic implications. The

extreme developmental changes that the brainstem and cerebellum undergo

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during fetal life pose a challenge for the characterization and definition of the

different malformations.

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The present review aims to demonstrate the normal development of the

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fetal brainstem and to present the main features required for diagnosis of its

anomalies according to available data in the medical literature.

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Keywords: fetal brain, fetal neurosonography, vermian hypoplasia, Joubert
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Syndrome, rhombencephalosynapsis, cerebellar hypoplasia, cobblestone

malformation, diencephalic-mesencephalic junction

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Introduction

The embryonic structures of the midbrain and hindbrain (MB-HB) and

their differentiation process into the brainstem and cerebellum have been the

focus of recent research in the fields of neurogenetics, developmental biology

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and fetal neuroimaging. The last classification system proposed and accepted

worldwide for MB-HB anomalies (either developmental or acquired) is mainly

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based on genetic, and biodevelopmental criteria and less on neuroimaging

parameters as its previous versions1 .

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Prenatal diagnosis of MB-HB anomalies is important due to the

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associated neurodevelopmental impairment and genetic implications of a
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significant number of entities. In contrast to the postnatal neuroimaging criteria

of most brainstem (BS) anomalies, which are well defined and frequently denote
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a genotypic correlation (i.e. pontocerebellar hypoplasia, Joubert syndrome and

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related disorders), the extreme developmental changes that the BS and

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cerebellum undergo during fetal life pose a challenge to the characterization

and definition of the different malformations.

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Recently we have established reference data on normal development of

MB-HB structures in sagittal views using sonographic multiplanar imaging.2

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These nomograms were applied in a further study, to fetuses with diagnosed

anomalies such as cobblestone malformation complex, Chiari-II malformation,

pontocerebellar hypoplasia, rhombencephalosynapsis, Dandy–Walker

malformation and vermian dysgenesis.3 Application of the new reference data

enabled accurate diagnosis and characterization of these entities, however,

diagnostic criteria for the main anomalies affecting the BS solely or in

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continuum with the cerebellum during prenatal life are still lacking. Specifically,

the medical literature is scarce regarding fetal midbrain normal and abnormal

development, and only a few reliable publications address this topic.

{Formatting Citation}

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The present article describes the main features enabling diagnosis of BS

anomalies in utero, according to available data in the medical literature and the

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molecular basis of normal development of the fetal brainstem.

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Embryologic aspects, molecular basis and neurosonographic features of

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normal development of the fetal brainstem throughout gestation
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The knowledge of basic cerebellar and brainstem ontogeny helps
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understand the pathophysiology of the different anomalies involving these

structures. A longitudinal groove, the sulcus limitans, appears in the lateral wall
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of the neural tube during the 4th week and divides it into ventral and dorsal
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halves, this process is called antero-posterior patterning. The mantle layers

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ventral and dorsal to the sulcus limitans thicken to form the basal and the alar

plates, respectively, containing motor and sensory neuroblasts. The future

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cerebellum will develop from the dorsolateral aspect of the alar plates, which
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fuse medially by 9 weeks and extends extraventricularly. The tegmentum of the

pons is derived from its ventral aspect. 4

A critical organizing center (the isthmus organizer) for cerebellar and BS

development occurs at the junction of the mesencephalon and metencephalon

in the region of the isthmus. 5 Abnormal location of the isthmus organizer results

in the formation of abnormal and/or rudimentary MB-HB structures. The HOXA1

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gene was described as involved in the antero-posterior (A-P) patterning
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process. Additional genes responsible for A-P patterning signaling are: Fgf8,

Fgf17 and Pax6 for the anterior forebrain, Pax6 and En1/Pax6 for the

diencephalic-mesencephalic junction and Fgf8, Fgf17, Gbx2 and Otx2 for the

midbrain-hindbrain junction – isthmus organizer 7

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The BS is formed by the mesencephalon and both divisions of the

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rhombencephalon, the metencephalon and the myelencephalon.

Developmental studies demonstrate that the cerebellar anlage derives from

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both the mesencephalon and the metencephalon. The cerebellar hemispheres

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(neocerebellum) are derived primarily from the metencephalon, while the vermis
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(palaeocerebellum) is derived from the mesencephalon. Neurons that

constitute the MB-HB structures are mostly generated in the lining

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neuroepitelium of the 4th ventricle walls. Early vermian formation requires genes

implicated in the function of the primary cilium / basal body organelle (PC/BB)
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such as NPHP1, AHI1, CEP290, RPGRIP1L, TMEM67/MKS3, ARL13B,

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CC2D2A and TMEM216.9 Other important genes involved in MB-HB formation,

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mediating migration of precursors out of the rhombic lip and the cerebellar

ventricular zone are PTF1A, FOXC1 and genes of the RELN pathway, O-
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glycosylation and tubulins.6

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During BS development, the pontine flexure appears at about 5

gestational weeks, the expansion of the 4th ventricle cavity displaces the alar

plate laterally and downwards and this division determines the location for the

neuron columns. The development of the midbrain, pons and medulla also

consists of direct and indirect migrations of cells from the periventricular

germinal zones.8 Normal dorso-ventral patterning of the MB-HB is required for

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normal vermian development and to avoid abnormal fusion of the cerebellar

hemispheres (i.e. rhombencephalosynapsis). Additionally, several genes are

responsible for normal axon pathfinding and the establishment of right

connections within the BS nuclei, such as tubulins, Joubert syndrome and

related disorders (JSRD) and ROBO3 genes.6 The axonal guidance process is

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of utmost importance for the ingrowth of fiber tracts, development of the

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reticular formation, and migration of young neurons from the rhombic lip and, at

last, the final location of the BS and cerebellar nuclei.

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It is interesting that although the rate of differentiation of neuronal groups

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in the cerebellar vermis exceeds those in the lateral hemispheres, the overall
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bulk growth of the midline sector of the cerebellum (12 weeks) lags behind that

of the hemispheres. These features are clearly identified by ultrasonography in

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the first trimester.8 The folia cannot be identified before 16-17 weeks.4 The

mature form of the inferior olivary nuclei does not become apparent until 22–27
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weeks.10 Vermian growth accelerates after 12 weeks, and impairment of this

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relatively late midline growth has been postulated to account, at least in part, for

vermian aplasias and hypoplasias. 11

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One of the major challenges of fetal brain imaging assessment is the

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transitional nature of the main structures and this is especially true regarding
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MB-HB structures. The first lumen to expand is the rhombencephalic ventricle

and it can be detected by high resolution ultrasound imaging by the 7th

gestational week (GW). This cavity continues to expand until the 9-10th week

and then starts to shrink, gradually assuming the typical form of the 4th

ventricle. Recently, the sonographic aspects of normal and abnormal 4th

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ventricle (4v) development have been described in detail by our group. The
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mesencephalic vesicle (future aqueduct) and the diencephalic vesicle (future

3rd ventricle – 3v) are the next to expand and also begin to shrink after a short

developmental period.13 These structures may be clearly depicted by 3D US

after 8-9 GW. By the end of the 1st trimester the ependyma and glioepithelium

lining of the 3v / aqueduct / 4v is completely developed and migratory neurons

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are highly prominent in the medulla and pons. Of interest, the midbrain is the

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only major part of the brain that develops directly from a primary brain vesicle.

The thin-walled mesencephalic vesicle encloses a cavity of some size and

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further thickening of the walls reduces this vesicle to form the cerebral

aqueduct. At the end of the fourth month, neurons descending from the

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developing cortex reach the midbrain and form bands on the superficial aspect
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of the nigral crescent, which rapidly increase in thickness and become the
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cerebral peduncles. The alar plates send cells to form the tectum, which

aggregate to form the paired superior and inferior colliculi.4 Additionally, the
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superior cerebellar peduncles are histologically distinct but not clearly depicted
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by US before 15-16 weeks.

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Transvaginal US studies in the first and early second trimesters identify a

clearly kinked Z-shaped fetal brainstem and the flexures mark structural
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divisions within the central nervous system. The mesencephalic flexure is the
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juncture between the future cerebrum and midbrain. The pontine flexure forms

the cavity eventually occupied by the fourth ventricle and cerebellum. The

cervical flexure separates the future spinal cord below from the brain above.15

The presence of the flexures is the first step in the process by which the

growing cerebellum obtains its position over the roof of the 4v by the 14th week.
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The cerebellum is then a thick, smooth structure overlying the posterior pons
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and medulla and is also depicted in axial and coronal views using transvaginal

probes.

After 13 GW the ventral portion of the pons ( a large number of

neuroblasts of the pontine nuclei, the pyramidal and pontocerebellar axons)

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present a remarkable increase in the number of cells, with significant antero-
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posterior growth of the basilar pons during the second trimester. The

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development of the pontine nuclei leads to a specific hyperechogenic pattern

that differentiates the anterior pons from the tegmentum (only fibers), seen

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during the late second and third trimester.

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With further growth, intense neuronal migration and reorganization of the
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hindbrain structures, the cervical, the pontine and the mesencephalic flexures

disappear leading to the mature brainstem macroscopic shape - in line with the
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spinal cord.17 This crucial step in the ontogenesis of the normal fetal BS occurs
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between the 14th and the 15th gestational weeks and by this time the cerebral
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aqueduct, the posterior aspect of the pons and medulla are continuous and

depicted as a straight line. These findings may be clearly depicted during

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3,18
neurosonographic studies and persistence of embryonic brain flexures after

15 weeks, is abnormal and considered a sign of severe cerebral dysgenesis.15

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The advent of 3D high resolution US allows better imaging of MB-HB structures

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in the fetus and reference ranges for their normal growth in the sagittal view

throughout gestation and their application for diagnosis of posterior fossa

anomalies are available.2,3,19 To the best of our knowledge, there are no studies

on the developmental anatomy of the midbrain tegmentum, the medulla

oblongata and on BS structures in the axial or coronal planes. The diagnosis of

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entities affecting these structures are based mainly on subjective analysis, case

series or postnatal data.

Prenatal diagnostic features of brainstem anomalies

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Joubert Syndrome and Related Disorders (JSRD)

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Joubert syndrome (JS) is a rare inherited cerebellar ataxia (1:80.000-

100.000 live births), first described in 1969 by Marie Joubert in siblings with

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vermian agenesis.20 The underlying pathogenesis lies in the defective function

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of the primary cilia (ciliopathy) which affect the development of the brain as well
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as kidneys, retina, liver and tubular bones.21,22 The molar tooth sign (MTS) was

described in 1997 as the pathognomonic imaging feature for the diagnosis of

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JSRD and it can be observed in lower axial views at the level of the midbrain:

thickened and elongated superior cerebellar peduncles (SCP), with a narrow

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pontomesencephalic junction, a deep interpeduncular fossa, and absent or

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dysplastic vermis.23 The MTS was first identified prenatally by MRI in the 3rd
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trimester , then by ultrasound in the 3rd trimester 25
and finally, recent

publications reported on clear features of JSRD (partial MTS) as early as 12

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gestational weeks in a high-risk fetus.26 Still, most cases are identified only by
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the presence of clear features of a vermian anomaly or when there is a family

history.27 Indirect signs have also been described in the literature and should

prompt a dedicated study of the fetal brain in order to rule out JS: abnormal

morphology of the 4th ventricle (4v) in axial (elongated antero-posteriorly rather

than latero-laterally – inverted proportions)12,28 and sagittal views (enlarged and

quadrangular 4v, and flat fastigium. Vermian dysplasia is identified by a small

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biometry and lack of the primary and secondary fissures. (Figure 1) Half of the

cases demonstrate an enlarged posterior fossa. Additional findings include a

cephalocele, renal cystic disease or polydactyly. Polymicrogyria and other

malformations of cortical development, corpus callosum agenesis, coloboma,

and increased nuchal translucency have also been described in JSRD.24,29

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Prenatal diagnosis is important for parental counselling regarding the generally

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poor prognosis (and regarding the autosomal recessive mode of inheritance of

most cases. 29 (Figure 1)

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Cobblestone Malformations (COB)
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The cobblestone malformations (COB) are a unique group of anomalies

caused by mutations of any genes involved in abnormal O-glycosylation of α-

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dystroglycan (POMT1, POMT2, POMGnT1, FKTN, FKRP, LARGE, B3GALNT2,

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B3GNT1, GALNT2, GTDC2, ISPD, TMEM5 and DAG1).30–32 The underlying

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mechanism leading to multiple coarse gyri with agyric regions, resembling

posterior pachygyria/agyria and anterior polymicrogyria is not a primitive

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neuronal migration failure as in lissencephaly type 1,33 but rather overmigration

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of neurons through the pial basement membrane into the arachnoid space,

resulting in the formation of an extracortical neuroglial layer, and a ‘cobblestone’

appearance of the brain surface. This layer also obstructs the subarachnoid

space, and together with a complex midbrain-hindbrain malformation leads to

hydrocephalus.34 Devisme et al reported that the cerebellar anomalies seen in

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COB are secondary to a similar pathophysiological process with disrupted

adhesion of developing granule cells to the pial basement membrane.34

COB are a continuum of recessive autosomal disorders with variable

clinical presentations ranging from Walker–Warburg syndrome (WWS) at the

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most severe end of the spectrum, to muscle–eye–brain disease and Fukuyama

muscular dystrophy, to congenital muscular dystrophy types 1C and 1D to limb-

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girdle (LGMD2I, LGMD2K, LGMD2M) muscular dystrophies. Severe cases are

characterized by major neurological deficits- profound intellectual disability,

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severe hypotonia, muscle weakness due to congenital muscular dystrophy, and

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a variety of eye abnormalities. We have recently reported a homozygous
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mutation in the DAG1 gene causing an unusual presentation of WWS with

tectocerebellar dysraphia features.32

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The prenatal diagnosis of COB is still a challenge, especially in early

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second trimester. Most of the reported cases identified in utero have a previous
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family history and/or are related to the most severe presentation: )

tetraventricular ventriculomegaly (hydrocephalus), very delayed sulcation,

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severe hypoplasia of the brainstem with kinking (z-shape boundaries) and

aqueductal stenosis, cerebellar hypoplasia with severe vermian dysplasia.

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30,35,36
The BS appears to be ‘stuck’ and encased within the neuroglial outer
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layer, preserved in its embryonic configuration of 7 weeks.37 Lacalm et al. also

described a thick outer echogenic band best seen in coronal views of the brain,

in place of the normal thin echogenic interface between the cortical surface,

MB-HB boundaries and the subarachnoid space ,with decreased pericerebral

spaces.37 All findings may be observed by dedicated neurosonography, but the

brainstem anomaly is more often detected by MRI studies and, although not
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pathognomonic, it is the most characteristic finding and a clue to the diagnosis.
38,39
Transvaginal US has an important contribution to early diagnosis. Callosal
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anomalies are reported in 80% of WWS. cases It is important to note that

mild cases of COB may be underdiagnosed during pregnancy. On the other

hand, in severe cases it may be difficult to differentiate from holoprosencephaly,

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tubulinopathies, other lissencephaly syndromes with cerebellar hypoplasia and
35,41,43

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aqueductal stenosis syndromes like L1-CAM. Additional findings are

midline facial clefts and visceral malformations (gastro-intestinal, urinary,

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cardiac, pulmonary). Ocular anomalies, although an essential part of the final

diagnosis, are not usually identifiable prenatally (retinal detachment, persistent

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primary vitreous vasculature, malformed orbits and cataract).44. (Figure 2)
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Pontocerebellar hypoplasia (PCH)

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The term pontocerebellar hypoplasia is frequently used in the medical

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literature as a descriptor of the reduction of volume of the cerebellum and pons.

This finding may be found as a component of several conditions affecting MB-

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HB structures. It has also been used in relation to a heterogeneous group of

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neurodegenerative autosomal recessive anomalies of prenatal onset as

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described by Barth in 1993, (PCH types 1, 2, 4, 5, 6, and 7) and diseases with a

non‐progressive course (PCH types 3 and 8). Prenatal diagnosis of most of

these entities have been published as case reports or case series, and at

present there are no absolute and defined criteria for their diagnosis using fetal

ultrasound or MRI.37,42,45–53
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The main challenges in the diagnosis of PCH are the absence of

additional brain anomalies and the fact that most cases are morphologically and

biometrically normal at the time of the second trimester anatomy scan (19-24

weeks). Hypoplasia (a small TCD) with superimposed atrophy of the cerebellum

and absence or significant reduction of the pontine prominence are the

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characteristic findings of PCH which may be detected in some cases only in the

3rd trimester. Moreover, the cerebellar hemisphere involvement is often more

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severe than the vermian anomaly and the degree of pontine hypoplasia is

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variable between different entities.27 PCH2 and PCH4 (mutations in TSEN54, in

most European cases) are considered part of the same disease process, which

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affects the brainstem and cerebellum during the late second trimester and
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presents more severely in PCH4.10 Even then, the characteristic “dragonfly
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appearance” observed in postnatal imaging (very flattened cerebellar

hemispheres with a relatively preserved vermis) has never been described

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prenatally.54,55 Prenatal clinical symptoms such as polyhydramnios and

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contractures are more frequent in type 4 and early postnatal death is often

reported, usually due to primary respiratory insufficiency. (Figure 3)

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Other types of PCH may be identifiable at earlier gestational ages,

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mainly by a small-for-gestational-age transverse cerebellar diameter.

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Interestingly, the cutoff of the TCD value at mid-gestation that requires

additional investigation or sonographic follow up is not determined in previous

publications. An abstract by Atallah et al, on the outcome of 499 fetuses with a

TCD below the 5th percentile presented, for the first time, that these fetuses are

at a very high risk for an unfavorable pregnancy outcome (intrauterine demise,

genetic anomalies, CNS and cardiac malformations and abnormal postnatal

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neurodevelopment), but no specific recommendations regarding cerebellar

hypoplasia were made.56

Adamsbaum et al. described the imaging features of PCH and presented

the absence of the pontine curvature as a universal abnormal feature that

predicts a poor neurological outcome.57 Graham et al. proposed the use of

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prenatal DTI / tractography to demonstrate the well-described feature of loss of

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ventral pontine neurons and transverse pontine crossing fibers, demonstrated in

previous neuropathology studies as early as 30 weeks.58,59 When PCH is only

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part of a syndrome which affects the fetal CNS globally, additional findings are

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almost always present and are usually detected before the MB-HB changes.
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The PCH in such cases, caused by mutations in the CASK gene or in

lissencephaly syndromes (mutations in RELN, VLDLR and ARX) represents a

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congenital malformation and,27,43 in these cases, the vermis is often more

severely affected than the cerebellar hemispheres. The neuroimaging features

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are described in the postnatal literature with very few case reports regarding
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prenatal diagnosis.
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Diencephalic-mesencephalic junction (DMJ) dysplasia

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Subtle anomalies of MB-HB structures secondary to defects in the

antero-posterior or dorsoventral patterning process have only recently been

consistently identified.7 The dysplasias of the diencephalic-mesencephalic

junction are underestimated causes of developmental hydrocephalus and share

phenotypical features with L1CAM and L1-CAM-like syndromes.27,60 The clinical

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presentation includes: severe cognitive impairment, postnatal progressive

microcephaly, axial hypotonia, spastic tetraparesis, and seizures.27

Severino et al published the only series on prenatal MRI diagnosis of

type-A DMJ in 13 hydrocephalic fetuses, in which the butterfly sign was

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detected in axial views of the midbrain in all cases: an enlarged dorso-ventral

axis and a deep interpeduncular fossa. It is interesting to notice that in DMJ

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malformations the interpeduncular fossa is not connected with the third

ventricle, although it seems to be using prenatal imaging. There is a thin

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anterior wall of the midbrain bulging into the interpeduncular cistern (invisible on

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fetal MRI due to resolution limitations, but is clearly depicted in postnatal MRI).
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Moreover, the whole exome sequencing analysis for not-DMJ abnormalities was

not performed in Severino et al. study and, therefore, their results on DMJ
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malformations should be evaluated with care. Sagittal images depicted a poorly

defined DMJ, an abnormal ventral position of the thalami with an enlarged

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massa intermedia and a poorly identified aqueduct. Vermian hypoplasia,

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pontine hypoplasia and kinking of the pontomedullary junction was present in

90% and aqueductal stenosis was confirmed in all cases.61 (Figure 4)

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Associated anomalies are frequent including callosal abnormalities and severe

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triventricular ventriculomegaly. The sonographic diagnosis of DMJ dysplasia is

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yet to be reported.

Pontine Tegmental Cap Dysplasia (PTCD)

The development of diffusion tension imaging –DTI (noninvasive

tractography) for detailed fiber tract anatomy enabled the characterization of

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disorders of axonal guidance as a new and significant category of human

genetic neurodevelopmental disorders.62

Pontine tegmental cap dysplasia is a rare cerebellar, brain stem and

cranial nerve malformation syndrome of poor prognosis, presenting with apnea,

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respiratory distress, developmental delay, ataxia, variable cranial nerve

involvement (V-IX) leading to ocular anomalies, corneal anesthesia, facial palsy,

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sucking and swallowing disorders and deafness.45 The etiology and pathogenic

mechanisms remain uncertain and the genetic basis is still unknown.27 In the

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medical literature, less than 60 cases of PTCD have been reported.63 Prenatal

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diagnosis has been described on only 4 patients.45 Theories suggest that the
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“cap” results from an embryonic failure of normal axonal guidance that leads to

failed connections within neurons, apoptosis, and false connections.64

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The main neuroimaging features include: ventral hypoplasia of the pons

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and a vaulted dorsal structure (the “cap”) which may be located at the middle
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third of the pontine tegmentum and projects into the fourth ventricle. (Figure 5)

Cerebellar involvement is present: vermian hypoplasia, and a small TCD

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secondary to hypoplastic cerebellar hemispheres.65 Although all findings are

detectable by ultrasound imaging, MRI studies allow better identification of the

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main features due to the high contrast between MB-HB structures and the CSF
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that envelopes them. Postnatal DTI studies demonstrate that the “cap”

corresponds to an ectopic bundle of transversely oriented fibers, with absence

of normal transverse pontine fibers.65 Extracerebral malformations such as

skeletal, cardiac, urogenital and facial anomalies have been described.45,63,66

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Rhombencephalosynapsis (RES)

RES is a very rare MB-HB anomaly caused by a genetic defect in the

isthmic organizer, leading to complete or partial absence of the vermis and

midline fusion of the cerebellar hemispheres and dentate nuclei. Superior

cerebellar peduncles are located close to the midline.67 It may occur in isolation

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or in association with a number of intra- and extracranial abnormalities.68–70 The

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clinical presentation is variable and depends on the severity of the RES

features, including ataxia, involuntary head movements, developmental delay

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and psychiatric disorders. Behavioral abnormalities are common in teenagers.

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In severe cases, death occurs in childhood, although there are reports of
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survival into adulthood.

The key features for the imaging diagnosis are (1) complete or partial
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absence of the cerebellar vermis and (2) continuity of the cerebellar hemi-
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spheres across the midline with fused dentate nuclei and an abnormally shaped
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4th ventricle.71 (Figure 6) Most of the prenatally reported cases refer to complete

RES where the 4th ventricle has globally small dimensions depicting a typical
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“diamond-shape” in axial plane, the vermian primary and secondary fissures are

not visualized and the fastigium is not identified on the sagittal views.72 Coronal
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views of the cerebellum demonstrate the typical continuous folial pattern. MRI
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studies identify a fused horseshoe-shaped dentate nucleus. Cerebellar

hypoplasia is a predominant feature in subjects with RES, although the TCD

may be within the normal range during the mid-second trimester. Brainstem

involvement includes pontine hypoplasia (up to 25% of cases), absence or

dysmorphic cerebellar peduncles (usually superior and middle) and midbrain

anomalies (50%) with aqueductal stenosis and fusion of the colliculi. Partial
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RES types have been described in only 2 case series and identified solely by

MRI in midgestation.73,74 Koprivsek et al. stated that US may be inadequate and

not reliable in the diagnosis of partial RES and Guleria et al. addressed the

differential diagnosis between this entity and some atypical forms of Chiari

malformation type II.75

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Additional CNS anomalies are frequently seen in RES cases, such as

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absence of the septum pellucidum, lobar holoprosencephaly, callosal anomalies

(75% thin and dysplastic), heterotopias and encephaloceles (less frequently).76

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Non-CNS associations like thymic hypoplasia, , cardiac anomalies, genito-

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urinary malformations, vertebral defects, cranio-facial dysmorphism, have also
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been reported.72 RES may appear as part of two specific syndromes /

associations: Gomez Lopez Hernandez (GLH - RES, trigeminal anesthesia and

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bilateral parieto-occipital alopecia with typical craniofacial anomalies including

hypertelorism, brachyturricephaly, midface retrusion and short stature) and

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VACTERL.69,77. Ishak et al. suggested that if a diagnosis of RES is made GLH

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syndrome, VACTERL association and holoprosencephaly should be excluded.

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The predominance of sporadic cases points to de novo dominant mutations,

although there have been reports of consanguinity and familial recurrences in a

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minority of families.
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Conclusion

Prenatal diagnosis of brainstem malformations is still a challenge that

requires knowledge in human developmental anatomy, genetics and imaging

recognition patterns. The present review resumes the most recent evidences
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and provides tools for the diagnosis and the differential diagnosis of the most

important group of anomalies, in order to support adequate management and

counseling for the families.

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LEGENDS OF FIGURES

FIGURE 1. Sonographic findings in JSRD. A, B) Abnormal 4th ventricle

appearance in axial views at 17 weeks (A) and normal (B): anteroposterior
diameter larger than the latero-lateral (A, asterisk), Thickened superior
cerebellar peduncles (A, arrowheads) and absent vermis (arrow). In
approximately 20% of the cases the cerebellar hemispheres are enlarged and

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the TCD is normal. B) normal 4th ventricle dimensions (asterisk) and superior
cerebellar peduncles (arrowheads); C) Axial views at the level of the midbrain
enhanced by VCI demonstrating the molar tooth sign in a 20-week fetus with

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JSRD; D, E) Sagittal views of the BS and the vermis in a 24-week fetus with
JSRD (D) and in a healthy fetus of the same age (E). Note the thickened
enlarged tectum with thin aqueduct (D, arrowhead) and the abnormal dysplastic

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vermis (arrow) and SCP. The SCP are horizontalized (90 degrees) with the
posterior aspect of the pons, configuring a typical abnormal 4th ventricle
quadrangular shape. In E, the vermis (arrow) and the 4th v are normal and the
SCP not seen in the midline. The tectum (arrowhead) is thin and straight and

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the aqueduct is patent and clearly seen. F) Enlarged hyperechogenic kidneys
frequently observed in fetuses with ciliopathies.
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FIGURE 2. Imaging features of CoB throughout gestation. A, B)
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Neurosonogram of a 29-week fetus with WWS; Axial view of the brain (A)
featuring irregular cerebellar surface with asymmetric juxtaposed hemispheres
and absent vermis (arrow), reduced extra-axial spaces with agyria
(arrowheads), enlarged dysmorphic lateral ventricles and abnormal insula
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(asterisk). Coronal frontal lobes view (B) demonstrating the extreme reduction in
the extra-axial spaces (arrowheads) with agyria and serrated cortical surface
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(arrows). The frontal horns of the lateral ventricles are enlarged and
dysmorphic. C) US midsagittal view of an 18-week fetus with WWS: kinked
hypoplastic BS (arrows) with an elongated and thickened tectum (asterisk) and
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very hypoplastic vermis (arrowhead). D, E, F) MRI imaging of WWS in a 28-

week fetus. (D) The same features seen in A with more severe hydrocephalus.
Note the severe hypoplasia and rectification of the midbrain (asterisks) in axial
view. (E) Abnormal 4v shape (asterisk) with hypoplastic vermis and enlarged
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posterior fossa (arrow). The pons is very flat presenting a posterior cleft and
abnormal signal (arrowhead). (F) Same features seen in C yet more severe BS
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hypoplasia (arrows). The aqueduct is completely obliterated (the tectum is fused

to the tegmentum- asterisk). The cerebellar vermis is very hypoplastic
(arrowhead).

FIGURE 3. Pontocerebellar hypoplasia in a 33-weeks fetus. A) The TCD was

measured on the 3rd centile for GA (according to Hill et al.). The cerebellar
findings are subtle – an abnormally shaped 4th ventricle in axial view –
enlarged, diamond-shaped (asterisk), no typical vermian hyperechogenicity is
seen between the hemispheres, the foliation is not clear. At this level, the 4v
looks closed and the CM is not enlarged. B) axial view of the posterior fossa in
a lower level – a key-hole sign is observed (communication between the CM
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and the 4v). Of notice is the abnormal foliation direction and the rectification of
the posterior aspect of the hemispheres with mild reduction in the antero-
posterior diameter (arrows). C) Sagittal view of the posterior fossa
demonstrating a flat pons with diminished A-P diameter, an abnormally shaped
4v and a dysplastic vermis that seems “blurred”. The primary fissure cannot be
seen.

FIGURE 4. MRI study of a 24-week fetus with diencephalic-mesencephalic

junction dysplasia type A. A) Midsagittal view of the brain demonstrates an

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hypoplastic vermis (asterisk) with a slightly enlarged cisterna magna, a flat pons
with an anterior pontine cleft (arrow) and an abnormal midbrain. B) Axial views
demonstrating the abnormal fusion of the midbrain with the hippocampus. C)

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The characteristic butterfly sign seen on axial views with anterior clefting of the
midbrain. Prenatal imaging lack in resolution to demonstrate the thin anterior
wall of the midbrain which bulges into the interpeduncular cistern and separates

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it from the midbrain cleft.

FIGURE 5. MRI features of pontine tegmental cap dysplasia in a 24-week fetus.

Ventral pontine hypoplasia and a vaulted dorsal structure projecting into the

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fourth ventricle (the “cap”) are well observed (asterisks). Vermian hypoplasia, is
depicted as well in this midsagittal view fo the brain.
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FIGURE 6. Prenatal imaging features of rhombencephalosynapsis. A, B) 24-
week fetus, note the typical convex posterior aspect of the cerebellum (A,
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arrows) and the small transverse diameter in axial views and the continuous
foliation in coronal views (B, arrows). The 4th ventricle is obliterated and no
echogenic vermis is seen in both views. C) Sagittal view of the brain of a 28-
week fetus with RES and hydrocephalus due to aqueductal stenosis. Note the
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enlarged tectum and the distal obstruction of the cerebral aqueduct (arrow), the
flat pons (asterisk) and the absence of the vermis with cerebellar hemisphere
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taking place, and abnormally-shaped 4th ventricle (arrowheads). A dilated third

ventricle is also observed, which extends posteriorly. The large interthalamic
adhesion (star) is another interesting dysmorphic feature. Despite the
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obstructive hydrocephalus, marked interthalamic adhesion hypertrophy may

overlap with diencephalosynapsis in RES cases and the differential diagnosis is
often difficult prenatally; D) 27-week fetus - sagittal view of the brain
demonstrating the dysmorphic enlarged tectum (arrowhead) suggesting
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mesencephalosynapsis (fusion of the colliculi), abnormal 4th ventricle (asterisk)

and absent vermis. In this case, the basilar pons is normal and there is no
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ventriculomegaly.
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