Dandy-Walker Syndrome: Brain

Developmental Disorder associated to

Hydrocephalus
Renzo Recella, Dwell Joy Armada, Joel Libao, Joseph Ryan Davalos, Mark Lawrence Zoilo
Department of Biology Students, College of Science,
Polytechnic University of the Philippines, Sta. Mesa, Manila

Abstract
Human brain development is a complex and orchestrated sequence of stages. Dandy-walker syndrome (DWS) is a
condition that affects the development of the part of the brain that coordinates movement, the cerebellum. Cerebellum is
located at the back of the underlying the occipital and temporal lobes of the cerebral cortex. It contains 50% of neurons in the
brain despite having only 10% of total volume of the brain. Individuals with DWS have hydrocephalus, buildup of fluid in
the brain, which causes increased brain size (macrocephaly). Cysts form in the fourth ventricle causing the ventricle to
enlarge and the part of the skull called the posterior fossa is abnormally large. These malformations often result in problems
with movement, coordination, intellect, and other neurological functions. This study features articles that associates DWS to
hydrocephalus how abnormal brain development cause enlargement and malformations in individual.
Keywords: Dandy-walker syndrome, cerebellum, abnormal brain development, hydrocephalus

Introduction
Centuries of sustained research remains unclear
and baffled brain scientist and still have little
understanding on how a brain, a three pound organ
and the seat of all human activity works (Yuste and
Church, 2005). Brain is an organ that serves as the
center of nervous system in all vertebrate and most
invertebrate animals. In humans, it has more
developed cerebral cortex and is one of the largest
and complex organs in human body and has been
called the most complex object in the known
universe (Rajeev, 2012). Human brain complexity
has made it difficult to study many brain disorders in
model organisms (Lancaster et al., 2013).
The development of the brain occurs with the
interaction of synchronized processes, undergoes
complex and orchestrated sequence of stages rather
than by simply growing through changing in a shape
of a small swelling at the front of the nerve cord to a

complex areas and connection in the early

embryonic stage (Lenroot and Giedd, 2006). Brain
development begins with the formation of
specialized fold of ectodermal tissue called neural
tube and by expansion of neuroephitelium to
produce radial glial cells that divides in the apical
surface within the ventricular zone to also produce
neurons and intermediate progenitors (Lenroot and
Giedd, 2006; Lancaster et al., 2013). The
intermediate progenitors and neurons populate and
migrate to adjacent subventricular zone, which is
divided to inner subventricular zone, and outer
subventricular zone by inner fiber layer, and
intermediate zone respectively to fill specific layer
within the cortical layer. Brain development in the
first 2 years after birth is very essential. Volumes of
brain substructure are known to change during
development. But with this short period of time,
brain growth plays an important role in

2
neurodevelopmental disorders (Knickmeyer et al.,
2008).

The cerebellum, in newborn human is

considered vulnerable because of the rapid growth at
that time when a period comparable in the
developing animal (Biran et al., 2011). The
cerebellum is one of the first to begin differentiation,
but still one to achieve maturity late. It also undergo
rapid changes including changing its size and to
reorganize its cortical layer during late fetal and
postnatal development and continues to change for
months after birth (Friede, 1972). These
developments of cerebellum can be classified and
describe in 4 stages. Louie and Glesson (2005)
explained the 4 stages of cerebellum development as
the characterization of cerebellar territory at the
midbrainhindbrain boundary, the formation of two
compartments for cell proliferation, migration of
external granule layer cells to processes of Bergman
glia and to their final position in the internal granule
layer and last is the establishing of cerebral circuitry
and further differentiation.

important in the development of the signaling center

that is responsible for patterning mesencephalic and
metencephalic regions of the vertebrate brain
(Dworkin et al., 2012). Cell fate in the cephalic
neural primordium is tightly controlled by feedback
inhibition of an organizer in the midbrain-hindbrain
boundary and this organizer will produce fibroblast
growth factor which is important to mimic, organizer
activity in the midbrain and anterior hindbrain
patterning (Rhinn and Brand, 2001). Patterning of
the neural primordium also involves special groups
of cells which are called neuroephitelial organizer
which also controls the cell fate of the surrounding
cells by producing secreted molecules. Once the
proper positioning of organizer is done, Fgf8 and
Wnt1 proteins from the organizer are being secreted
and functions as an organizing influence in the
surrounding neural tissues. Rhinn and Brand
(2001) ; Louie and Gleeson (2005) discussed
restricted expression of secreted factors such as
Fgf8, Wnt1, homeobox proteins En1 and En2 and
the paired box genes Pax2 and Pax 5 and the role of
fibroblast growth factors in early specification
midbrain-hindbrain structures and boundary. They
states that Fgf8 and Wnt1, these fibroblast
promoting factors functions as to mediate organizing
activity and maintaining expression of En genes.
Fgf8 is defined as anterior limit of hox gene
expression and is required for the maintenance of
marker gene expression in the midbrain and isthmus
and is a crucial molecular component in the
midbrain-hind brain boundary and the feedback
inhibition mentioned before has evolved to control
their activity.

The first stage in the development of cerebellum

is the characterization of the cerebellar territory at
the midbrain-hindbrain boundary. Formation and
maintenance of the midbrain-hindbrain boundary is
characterized by the hierarchal program of gene
expression initiated by fibroblast growth factor 8
(Fgf8), along with cellular morphogenesis,
culminating in the formation of the tectal-isthmocerebellar structures and the isthmic organizer
located at the midbrain-hindbrain boundary is very

The second stage in cerebellum development is

the formation of two compartments for cell
proliferation. The development of forebrain, facial
structures, spinal cord and the hollow center will
become brain and will form the ventricles and
around these ventricles forms the proliferative zones
which will give rise to young neurons (Lenroot and
Giedd, 2006). This two compartments are known as
the Purkinje cells and the granule cells precursors.
Purkinje cells, one of the largest neuron in the

Cerebellum Development and Dandy-Walker

Syndrome associated to Hydrocephalus
Human brain has many parts but will focus more
and involved only on the cerebellum and its relation
to Dandy- Walker syndrome resulting to
hydrocephalus. Cerebellum is located at the back of
the underlying the occipital and temporal lobes of
the cerebral cortex and contains 50% of neurons in
the brain despite having only 10% of total volume of
the brain (Kneirim, 1997).

3
human brain, along with deep cerebellar nuclie
formed in the roof of the fourth ventricle. Granule
cell layer and the precerebellar nuclie cells are
formed in the rhombic lip (Louie and Gleeson,
2005). Purkinje cells migrate outward and form a
monolayer in the cortex whereas the granule neuron
forms the external granule layer by migrating to the
surface of the developing cerebellum. The external
granule layer in the developing cerebellum consists
of neural progenitors from rostral rhombic lip which
is located in the hindbrain circling the opening of the
fourth ventricle that give rise to the granule neurons
of the cerebellum (Lin et al., 2001). Next and the
third stage after the cell proliferation is the inward
migration of the external granule layer cells to the
Bergman glia processes which plays an important
role in the dendritogenesis, synaptogenesis,
maturation of cerebellar purkinje cells and migration
of granule cells in the early cerebellum development
(Louie and Gleeson, 2005). Bergman glia is also
important in synaptic pruning, which is the
elimination of synapse that occurs during early
childhood and puberty.
The final stage of cerebellum development is the
establishing of cerebellar circuitry and for the further
differentiation. Purkinje cells form the heart of
cerebellar circuitry. Purves et al. (2001) discussed
the circuit events occur in the cerebellum. Dendrites
form a molecular layer from single layer of purkinje
layer and extensively branch in the right angle with
the parallel fibers. With this formation, purkinje cells
receive large numbers of parallel fibers and direct
modulatory input and numerous synaptic contacts
from a single climbing fiber. The climbing fiber
regulates movement of the mossy parallel fiber of
the granule cells in the connection to purkinje cells.
They also state that this circuit is repeated over and
over through the course of every subdivision of
cerebellum and this modulation of signal flow
provides basis for real-time and long-term regulation
that includes motor learning.
The cerebellum is a supreme model to study in
the neurogenesis and circuit assembly because of its

morphologically unique brain structure that is made

up of detailed set of folia separated by fissures
(Sundarov and Joyner ,2007). Recent evidence states
that cerebellum participates in higher order functions
such as cognition, emotion and language processing,
proprioceptive motor and autonomic functions. But
with this long developmental process, the
cerebellum creates opening and is highly susceptible
to disruption during embryogenesis resulting to
disorders and diseases (Wang and Zoghbi, 2001).
One of the disorders is the Dandy-Walker Syndrome
(DWS), which can be either inherited or
developmentally caused. Dandy-Walker Syndrome
is a rare disorder characterized by the congenital
malformation of the neural tube and localized defect
in the differentiation of the hindbrain resulting to
the absence or having small size of the cerebellar
vermis, cyst formation in the fourth ventricle and
abnormally large size posterior fossa (Kollias, 2014).
Dandy-Walker Syndrome is commonly associated
with hydrocephalus because the affected individuals
have a buildup of fluid, specifically the
cerebrospinal fluid in the brain (hydrocephalus)
which causes an increased in the head size
(macrocephaly). This abnormal accumulation of
cerebrospinal fluid results in the widening of the
ventricles in the brain. Hydrocephalus occurs up to
80% in the individuals with Dandy-Walker
Syndrome but there are many cases and accounts
where there is no enlargement of posterior fossa
which led to having the Dandy-Walker variant, a
lesser type of Dandy-Walker syndrome compare to
the classic Dandy-Walker malformation, although
the use of this term is been discouraged (Bernardino
et al., 2015).
History, Definition and Classification of DandyWalker Syndrome
Dandy-Walker syndrome was first introduced in
1887 by Sutton and further characterized by Dandy
and Black fan in 1914 followed by Tagart and
Walker in 1942. (Kumar et al., 2010). Benda finally
labeled this disease as dandy walker in 1954. DandyWalker syndrome is defined by hypoplasia and

4
upward rotation of the cerebellar vermis and cystic
dilation of the fourth ventricle. Affected individuals
often have motor deficits such as delayed motor
development, hypotonia, and ataxia; about half have
mental retardation and some have hydrocephalus.
DWS is a heterogeneous disorder. The low empiric
recurrence risk of approximately 1 to 2% for
nonsyndromic DWM suggests that mendelian
inheritance is unlikely (summary by Murray et al.,
1985). It is a rare intracranial congenital abnormality
that affects the cerebellum and some of its
components; particularly cerebellar vermis, fourth
ventricle and is characterized by an enlarged
posterior fossa. (Kumar et al., 2010).
Dandy-Walker complex has several variants,
Dandy-Walker malformation (DWM) encompasses
cystic dilatation of the fourth ventricle, complete or
partial agenesis of cerebella vermis and enlarged
posterior fossa (Willacy, 2011) while Dandy-Walker
variant (DWV) comprises cystic posterior mass with
variable hypoplasia of the cerebella vermis and no
enlargement of the posterior fossa. However, the
third variant mega-cisterna magna comprises
enlarged cistern magna with normal cerebellar
vermis and fourth ventricle. The clinical
manifestations include psychomotor and growth
retardation, hypotonia, strabismus, myopia, a short
neck, microcephaly, brachycephaly, hypertelorism,
antimongoloid slant of palpebral fissures, globulus
large nose, large mouth with down turned corners,
poorly lobulated ears, high arch palate, cleft palate,
small hands and feet, clinodactyly, and the
brachymesophalangy of the little fingers. Although it
is said that clinical examination cannot replace any
imaging modalities, DWM is such a condition that
require imaging modalities to diagnose the disorder.
Even though there are many signs, none of these are
characteristic to diagnose individuals as DWM and
diagnosis is solely based on imaging techniques. The
present manuscript reports a case encountered in our
clinic which was revealed as Dandy-Walker
malformation by MRI. (Kumar et al., 2010). Up to
now, further explanations and studies are being made

to support the ideas and explanation of the first

people who studied about Dandy-Walker syndrome.
Brain development in Dandy-Walker patients
Signs and Symptoms of Dandy-Walker Syndrome
Possible Medication
After knowing the symptoms or signs of having
this abnormality, this part will elaborate the medical
processes which are used for diagnosis. This part
also shows related treatments for associated
problems. Dandy-Walker malformation is best
diagnosed with the help of ultrasonography (US) and
magnetic resonance imaging (MRI). US may be the
initial examination performed because it can be done
portably and without sedation, as well as allowing
multiplanar imaging. US, however, is limited
because it is
heavily operator-dependent.
Abnormalities such as the gyral, dural, tentorial, and
skull anomalies that accompany Dandy-Walker
malformations are not clearly depicted by US. The
introduction of modern imaging techniques,
specifically MRI, has radically changed the
evaluation of symptoms related to the posterior
fossa. MRI is usually performed for detailed
evaluation of Dandy-Walker malformation lesions
and complications after the diagnosis is suspected
using computed tomography (CT) and US. MRI can
best define the relationship between the cyst and the
fourth ventricle, and it can detect vermian rotation
and the signs of vermian dysgenesis. MRI is
relatively expensive. High-quality MRI scans
require patient cooperation or sedation. MRI allows
surgeons to accurately view the cerebellum and
associated structures, determine which form the
malformation has taken, and gauge the progress of
the malformation. MRI also demonstrates which
space should be shunted first. Recently, MRI has
been frequently used for diagnosing fetal
craniospinal anomalies. Since it can distinguish
between hydrocephalus associated with DandyWalker and hydrocephalus associated with other
etiologies, CT scanning is also useful in Dandy-

5
Walker malformation; however, it exposes the infant
to ionizing radiation. Clearly distinguishing the
subtypes of Dandy-Walker complex on axial CT
images is difficult. In addition, evaluating subtle
supratentorial
pathologies
and
associated
abnormalities on CT scans may not be easy because
its routine use is constrained by the axial plane. The
classic abnormal findings of Dandy-Walker
malformation described on cranial CT and MRI can
also be demonstrated on cranial sonography. US is
routinely used during the antenatal period as a
screening method, and it is particularly used for
postnatal follow-up studies of hydrocephalus. US
evaluation of posterior fossa cystic abnormalities in

the newborn is best accomplished via a

posterolateral fontanelle approach or through the
cisterna magna posteriorly. Plain radiography has
been primarily used in the evaluation of shunt
malfunction as well as for diagnosing associated
anomalies (Incesu, MD., 2013). Medication for
DWS is not a one way treatment it includes several
medications. Studies have not yet discovered that
there is an individual process that could stop all the
abnormalities and associated problems. Treatment
for individuals with this abnormality, Dandy Walker
Syndrome, generally consists of treating the
associated problems (Bethesda, MD., 2014).

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