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260
ABC
DEF
GH I
Figure 7–14.
strual weeks of gestation ( A–C ) with MRI confirmation at 29 weeks of
gestation ( D–F ) and following delivery ( G–I ). The clinical course was
complicated by refractory epilepsy. Note the difference in the size of
the cerebral hemispheres and lateral ventricles. The corpus callosum is
thick ( C, I ), and the vermis not observed in the midline ( E, I ). Abnormal
sulcation in the left hemisphere is suggested on fetal images and clearly
depicted in both hemispheres on postnatal MRI ( G, H ). (Courtesy of
Dr. Mauricio Herrera, Bogotá, Colombia.)
Chapter 7 Malformations of Cortical Development
Hemimegalencephaly diagnosed by US at 28 postmen-
AB
Figure 7–15. Multiple cardiac rhabdomyomata in a fetus with tuberous
sclerosis. (A) Fetal US at 26 weeks’ gestation shows the presence of at
least four intracardiac tumors ( arrows ). (B) Coronal view of the heart at
30 weeks shows the cardiac rhabdomyomata ( arrows ).
of cardiac rhabdoyomata is highly suggestive of TSC
Figure 7–15 ).
(
It has been detected as early as 18 weeks gestation.
77
At prenatal US the affected hemisphere shows increased
volume, ventricular enlargement, abnormal texture, and
occasional calcifications ( Figure 7–14
). The smaller hemisphere is compressed and distorted by the enlarged one,
and characteristically abnormal findings are also present. 78
Note that normal fetuses can have a minimal 2 mm asymmetry at 20 to 22 postmenstrual weeks. 79
Prenatal US findings can be confirmed by MRI
( Figure 7–14 ). Differential diagnosis includes intracranial
tumor or bleed and infections.
Prenatally diagnosed cases are offered pregnancy termination.
Tuberous Sclerosis Complex
Synonyms
Tuberous sclerosis, TSC, Bourneville disease, epiloia, phakomatosis TS
Definition
Tuberous sclerosis complex (TSC) is a neurocutaneous
syndrome characterized by abnormal proliferation of
neurons and glia in the form of hamartomata or lowgrade tumors with accompanying anomalies of migration and differentiation. The manifestations of TSC
are not limited to the brain but usually involve other
systems, particularly the skin, eyes, kidneys, lungs, heart,
blood vessels, and bones. In the fetus, the presence
Incidence/Prevalence
The prevalence is estimated to be between 7 and 12 cases
per 100,000 live births, with more than half of these cases
undetected prenatally.
80
The total population prevalence
figures have steadily increased from 1 in 150,000 in 1956,
to 1 in 100,000 in 1968, to 1 in 70,000 in 1971, to 1 in 34,200
in 1984, to the present figure of 1 in 12,500 in 1998 .
Etiology and Pathogenesis
TSC is caused by mutations of the TSC1 gene on chromo-
81
some 9
or of the TSC2 gene on chromosome 16. 82 This
autosomal dominant disease expresses the following two
successive mutations: A germ line mutation produces a
loss of heterozygocity in one of the alleles, followed by a
somatic mutation of the other allele.
83
TSC1 and TSC2
encode for two proteins called hamartin and tuberin,
respectively. Hamartin and tuberin are tumor suppressors acting as inhibitors in the mTOR cascade pathway.
Hyperactivation of this pathway results in abnormal cell
growth and proliferation.
84
Although most of the cases are
due to sporadic mutations in TSC2, TSC1 mutations are
more common in familial cases.
Pathology
TSC may affect the brain in different forms. The name
of the disease originates from the presence of firm cortical masses with dimpling resembling potatoes with eyes.
Similar nodules may be found in the periventricular zone.
The tubers are composed of large, poorly differentiated
cells of neuronal and glial origin. Similar cells may be
found in the white matter. Abnormal cell differentiation
may also produce benign giant cell astrocytomas. In the
Chapter 7 Malformations of Cortical Development
261
fetus, the only other organ frequently involved (in up to
50% of cases) is the heart by the development of rhabdomyomata.
In 1986, Muller et al 88 reported the first US prenatal
diagnosis of a fetus at 26 weeks with brain involvement.
Since then a large number of case reports and small series
of fetuses with TSC stigmata have been published.
Risk of Recurrence
TSC is transmitted as an autosomal dominant trait with
high penetrance but variable expression, which may cause
mildly affected individuals to be undiagnosed. The vast
majority of cases are sporadic (
prenatal diagnosis or the birth of an affected patient, both
parents should be evaluated for the presence of subclinical
disease.
Table 7–4 ). Following the
Eight groups have studied the implications of the diagnosis of cardiac rhabdomyomata
89,96
majority of patients, the diagnosis was made relatively late
in pregnancy, the mean time of diagnosis ranging between
26 and 30 postmenstrual weeks of pregnancy. Multiple
rhabdomyomata were found more frequently than single
ones (72% vs 28%); only 23% required postnatal medical or
surgical treatment, and the vast majority decreased in size
after delivery. The risk for a fetus with rhabdomyoma to
suffer from TSC in the whole group was 75%, and a familial
Sonographic Diagnosis
The reported incidence of cardiac tumors in fetuses at fetal
echocardiography is 0.14%; rhabdomyomata represents
>90% of them. 85 The first prenatal diagnoses of TSC were
reported by DeVore et al
and colleagues based their diagnosis on the second-trimester detection of cardiac rhabdomyomata in a fetus at
risk. The first examination at 18 postmenstrual weeks was
considered normal, but by 22 postmenstrual weeks, the
presence of cardiac tumors was evident.
86
and Crawford et al. 87 Crawford
87
history was obtained in 17%. The risk for developmental
disease was available from three studies showing that 20
out of 47 children (42.5%) were affected. Affected children
were diagnosed either before or after delivery. Tworetzky
93
found neurodevelopmental deficits in 85% of chil-
et al
dren diagnosed before or after delivery.
Isolated reports on the US appearance of TSC-related
brain lesions have been published. In most cases the
findings were observed in patients at high risk for TSC
(familial history or presence of rhabdomyomata).
Mirkin and colleagues
98
reported on the presence of a
Table 7–4. PUBLISHED SERIES ON FETUSES WITH PRENATAL DIAGNOSIS OF CARDIAC RHABDOMYOMATA
( Table 7–4 ). In the
88 , 97 – 99
Number
Author (Year)
Pipitone
89
et al
(2002)
D’Addario
90
et al
(2002)
Gamzu et al
(2002)
Bader et al
(2003)
Tworetzky et
93
al
(2003)
Fesslova et
94
al
(2004)
Chao et al
(2008)
Saada et al
(2009)
Total 170 15–38 47 single,
IUFD, intrauterine fetal death; MRI, magnetic resonance imaging; NND, neonatal death; NS, not stated; TOP, termination of pregnancy; TSC, tuberous
sclerosis complex.
of Fetuses
9 27–36
6 23–37
91
18 21–33
92
20 19–37
42 15–38
13 21–36
95
11 18–39
96
51 21–37
Week of
Diagnosis
Mean 30.0
Mean 30.0
Mean 27.1
Mean 28.4
Mean 28.5
Mean 26.0
Mean 27.5
Mean 27.1
Single,
Multiple Outcome
1 single,
8 multiple
3 single,
3 multiple
12 single,
6 multiple
2 single,
18 multiple
9 single,
33 multiple
5 single,
8 multiple
5 single,
6 multiple
10 single,
41 multiple
123 multiple
9 delivered
(1 NND)
6 delivered 1 (died) 3/60/6 NS
12 delivered,
6 TOP
18 delivered
2 TOP-IUFD
34 delivered,
8 TOP-IUFD
9 delivered,
4 TOP
8 delivered
(2 NND),
3 TOP-IUFD
25 delivered,
26 TOP
121 delivered
(3 NND),
49 TOP-IUFD
Need for
Treatment
5 7/80/9 NS
0 7/123/18 NS
7 15/194/20 6/18
8 33/4210/42
0 9/112/13 5/9 2 neurosurgery
2 3/62/11 NS
5 (1 died) 39/518/51 9/20 With MRI
28/121 116/15529/170 20/47
TSC in
Family
Neurodevelo pmental Delay
85% (of prenatal +
postnatal group)
+ 67% With MRI
– 33%
262
Figure 7–16. Brain transvaginal sonography (TVS) images in a fetus with tuberous sclerosis at 28 postmenstrual weeks (same patient as in Figure 7–14 )
show multiple parenchymal echogenic nodules ( arrows ). (A ) Coronal section at the level of the frontal horns. (B) Paramedian section lateral to the lateral
ventricle.
Chapter 7 Malformations of Cortical Development
AB
large subependymal tumor diagnosed at 27 postmenstrual
weeks that was resected after birth and found to be a giant
cell astrocytoma. The diagnosis of TSC was only made at
4 years of age.
In fetuses referred because of multiple cardiac rhab-
domyomata (see
Figure 7–15 ), the diagnosis of brain involvement is usually possible when multiple bilateral parenchymal
and periventricular echogenic nodules are present 77 ( Figure
). Milder brain involvement may be very difficult or
7–16
even impossible to visualize (
Figure 7–17 ).
MRI Diagnosis
Many authorities
than US for the diagnosis of TSC brain lesions, but this
issue has never been studied in an unbiased way.
A
100 , 101
consider fetal MRI more effective
B
The largest published case series included 51 patients
referred for fetal echocardiography because of the presence
of cardiac rhabdomyomata during second- or third-trimester US examinations.
96
Although all the patients underwent
a detailed US examination, the results of the examinations
were not mentioned, and only data on fetal brain MRI were
included. MRI was performed at a mean gestational age of
30 postmenstrual weeks (range 24–37 weeks), brain lesions
were found in 25 (49%) patients, and 21 chose termination
of pregnancy (TOP), with autopsy positive for TSC in all
of them. MRI was considered normal in 26 (51%) patients,
5 underwent TOP, and TSC was diagnosed in 3. There
were 25 deliveries, including four with positive MRI findings. Neurological complications were reported in 45% of
the studied patients (9/20) and included seizures, mental
retardation, nodding spasms, and language retardation;
normal prenatal and even postnatal MRI did not rule out
the development of neurological complications at latter
96
( Table 7–4 ).
stages
Implications for Sonographic Screening,
Including Earliest Recognition
The presence of cardiac rhabdomyomata, particularly
when multiple and large is highly indicative of the presence of TSC. In these patients a detailed neurosonographic
examination and/or brain MRI are indicated. Although
early second-trimester diagnosis may be posible,
93 , 102
it
should be remembered that in more than two-thirds of
cases the diagnosis is made after 24 postmenstrual weeks
( Figures 7–15 , 7–16 , and
7–17 ).
Figure 7–17. Tuberous sclerosis at 25 postmenstrual weeks in a fetus
with multiple cardiac rhabdomyomata and no familiar history. (A)
Apparently normal coronal transabdominal view. ( B) Transvaginal coronal
section showing the presence of at least one parenchymal nodule ( arrow ).
Implications for Targeted Examination
The role of fetal imaging in the diagnosis of TSC will
become secondary following the introduction of molecular
tests for deletion/duplication analysis of TSC1 and TSC2
Chapter 7 Malformations of Cortical Development
103
genes.
the disease is suspected early in pregnancy or when one
of the parents is known to be affected.
Prenatal molecular diagnosis may be used when
103
When the suspicion of TSC is raised during the late second trimester
or third trimester, a dedicated US or MRI examination,
when positive, will continue to be the faster way to reach
the diagnosis.
Prognosis
TSC is a disease with multiorgan involvement but with a
wide range of severity. The classic clinical triad of facial
angiofibromas, mental retardation, and seizures is present
in 30% of the patients. Mental retardation is present in
50% to 80% of patients. When diagnosed during fetal life
or early infancy, neurodevelopmental disease may affect as
much as 85% of patients.
93
Obstetric Management
The prenatal diagnosis of TSC poses a serious dilemma
regarding continuation or termination of pregnancy, particularly when one of the parents is affected. Termination
of pregnancy should be considered when legally possible
and based on parents ’ desires. Postnatal neurosurgery may
be needed to resect epileptogenic nodules or when giant
cell astrocytoma produces hydrocephaly.
MALFORMATIONS DUE TO
ABNORMAL NEURONAL MIGRATION
Lissencephaly Overview
Lissencephaly means “smooth brain.” It describes a smooth
pathologic appearance of the brain surface that lacks the
normal gyri and sulci. There is spectrum of brain surface
appearances ranging from completely smooth (agyria)
to partially smooth with abnormally large gyri (agyria/
pachygyria). Lissencephaly implies a major abnormality of
neuron migration, secondary failure of normal gyration,
and results in major neuromotor abnormality. There are
two main processes or mechanisms by which migrational
abnormality occurs: first, classical or type 1 lissencephaly
and, second, type 2 or cobblestone cortex lissencephaly. In
both there is major disruption of normal neuronal migration that starts in the first trimester, but the genetic and
molecular disturbances are different. In type 1/classical,
there is failure of neurons to migrate to the surface. In type
2, migration occurs but is not stopped at the surface by
the pia limitans, allowing neurons to overmigrate into the
subarachnoid space, where they cluster and partially cover
brain surface vessels, resulting in a finely nodular surface
that has been described as cobblestoned. The surface
nodularity is so fine that to uninitiated observers, the brain
surface appears smooth, but the partially covered surface
vessels are more readily apparent.
There are two additional considerations. First, the
genes and molecular mechanisms that control neuronal
migration also have functions in the normal development
of other tissues and organs. As a result, when they malfunction, it is common to see developmental abnormali-
263
Table 7–5. PATIENTS AT HIGH RISK OF ABNORMAL
NEURONAL MIGRATION
Familiar
history
Abnormal
US findings
MCD, malformations of cortical development; US, ultrasound.
Parents or siblings with MCD
Parents or siblings with non-diagnosed
epilepsy
Maternal side siblings with MCD, epilepsy,
early death of males
Ventriculomegaly (including mild)
Suspected microcephaly or macrocephaly
Callosal anomalies
Agenesis of the septum pelucidum
Cerebellar anomalies
Ambiguous genitalia
Skeletal dysplasia
ties in other areas. For example, the genes associated with
type 2 cobblestone cortex also function in normal muscle
development. Fetuses with cobblestone cortex also have
abnormal muscle structure clinically expressed as congenital muscular dystrophy and apparent with abnormal serum
creatine kinase and abnormal muscle biopsy. Second,
many structures, such as the eyes, cerebellum, and corpus
callosum, are developing at the same time as neuronal
migration is occurring. As a result, a teratologic insult (eg,
infection) at a specific time can affect all of these structures
at their stage of development. Therefore, it is not unusual
to see MCD in association with abnormality involving the
eyes, corpus callosum, and cerebellum. A corollary is that
an abnormality detected in any of these structures should
lead to evaluation of the other simultaneously developing
3
areas.
The performance of a detailed neurosonographic
examination in search of migration disorders should be
performed based on familial or clinical indications
(
Table 7–5 ).
104
Lissencephaly/Subcortical
Band Heterotopia Spectrum
Synonyms
Classical lissencephaly, lissencephaly type 1 (LIS1),
X-linked lissencephaly, agyria/pachygyria, Miller-Dieker
syndrome (MDS)
Definition
Type 1 or classical lissencephaly (smooth brain) is characterized by failure of migrating neurons to reach the cortical
surface. As a result, there is total or partial failure to form
cerebral convolutions or gyri and sulci. Subcortical band
heterotopia (SBH) is a less severe phenotype of the same
disease characterized by partial failure of the neurons to
reach the cortex, resulting in a thin cortex with abnormal
sulcation and a second layer/band of neurons underlying
the outermost one.
264
Chapter 7 Malformations of Cortical Development
Incidence/Prevalence
In the period 1980 to 1988, the prevalence of lissencephaly
type I in the Netherlands was 11.7 per 1 million births.
There are no available data from other countries on the
incidence and prevalence of this disease.
105
Pathogenesis
Neuronal migration occurs during and following the period
of neuronal proliferation, starting at 6 to 7 postmenstrual
weeks of gestation and is essentially finished by 30 weeks ’
gestation in the cerebral cortex. Neurons migrate from the
ventricular and subventricular zone until they reach the
pia surface in 6 successive waves; two different varieties
of migration, tangential and radial, have been described.
Radial migration is responsible for the formation of most
of the cortex; tangential migration is the way used by the
interneurons to reach their place in the cortex.
2
In patients with lissencephaly radial migration is
disturbed between 11 and 13 postmenstrual weeks ’ gesta-
106
due to abnormal function of genes that affect key
tion
molecular processes, in particular platelet-activating factor
acetylhydrolase (PAFAH), doublecortin, and the glycoprotein reelin.
5
Different mutations affecting the same gene
will result in different phenotypes.
Etiology
Most of the known lissencephalies are transmitted as autosomal dominant or X-linked traits and only rarely as an
autosomal recessive trait.
The lissencephaly/SBH spectrum includes four different genetic types: LIS1 mutations, DCX mutations, ARX
mutations, and reelin ( RELN ) mutations (
LIS1 mutations are the most frequent and result from
deficiencies in PAFAH and affect the normal function
of the cytoskeleton. Isolated lissencephaly and MillerDieker syndrome have a similar locus at 17p13.3. Mei
107
identified mutations in the LIS1 gene in 20 (44%)
et al
of 45 patients with isolated lissencephaly. In 19 (76%) of
25 patients in whom FISH and direct sequencing had failed
to detect mutations, multiplex ligation dependent probe
amplification assay identified 18 small genomic deletions
and 1 duplication.
107
Overall, small genomic deletions/
duplications represented 49% of all LIS1 alterations identi-
fied, and LIS1 involvement was demonstrated in 39 (87%)
of 45 patients. Cardoso et al
108
completed a physical and
transcriptional map of the 17p13.3 region from LIS1 to
the telomere. Using FISH, they mapped the deletion size
in 19 children with isolated lissencephaly sequence (ILS),
11 children with MDS, and 4 children with 17p13.3 deletions not involving LIS1. They showed that the critical
region that differentiates ILS from MDS at the molecular
level can be reduced to 400 kB. Using somatic cell hybrids
from selected patients, the authors identified eight genes
that are consistently deleted in patients classified as having
108
In some reports, patients with large deletions and
MDS.
truncations of the LIS1 mutations had diffuse or severe lis-
sencephaly, whereas those with less severe LIS1 mutations
had posterior pachygyria only or posterior-predominant
Table 7–1 ).
subcortical band heterotopia or even a normal brain MRI
109
scan.
Others failed to find a similar correlation but
instead found that the degree of severity correlates only
with the degree of agyria and cortical thickening and with
the standardized grading used currently in the interpretation of MRI.
110
DCX mutations, located at Xq22.3, produce a defi-
ciency in doublecortin, a protein essential in the formation
of microtubules.
111
This X-linked lissencephaly results in
males with lissencephaly of various grades of clinical severity, whereas affected females are clinically less affected,
though they may have a double-cortex pattern or a normal
MRI.
Aristaless-related homeobox protein ( ARX ) mutations
are also located at Xq22 and result in lissencephaly with
2
abnormal genitalia and anomalies of the corpus callosum
(XLAG). In XLAG, the tangential neurons are affected. The
severity of the malformation is determined by the size and
the severity of the mutation. Conservative substitution in
the homeo domain causes the Proud syndrome (X-linked
mental retardation, callosal agenesis, and abnormal genitalia). Other mutations cause less severe phenotypes.
RELN mutations cause lissencephaly with cerebellar
hypoplasia. Reelin deficiency results in an abnormal stratification of the cortex with the first waves of neurons positioned in proximity to the pia surface. Abnormal migration
in the cerebellum produces cerebellar hypoplasia. An
autosomal recessive pattern of inheritance may be present
in some of the affected families.
113
Pathology
In the classical form of lissencephaly, brain weight may be
normal or low, and the brain has a “figure 9” shape with
an open sylvian region because the frontal and temporal
opercula fail to grow over the insula. However, variations
in severity occur ranging from complete agyria to varying degrees of agyria and pachygyria. A morphological
classification was developed to describe differences in
severity of the gyral malformation. Lissencephaly grade 1
is complete agyria; grade 2 has widespread agyria with a
few sulci restricted primarily to the frontal and temporal
poles and basal frontal lobe; grade 3 has extensive areas
of both agyria and pachygyria in which pachygyria is
more common frontally and agyria posteriorly; and grade
4 has widespread pachygyria without areas of agyria
(
Figure 7–18 ).
There are only a few reports of brain pathology in
fetuses and newborns with lissencephaly/SBH spectrum,
most with LIS1 but also XLIS. A thick four-layer cortex is
described composed of a superficial hypocellular “molecular” layer I, covering a cellular zone of heterotopic large
pyramidal neurons in layer V and VI of normal cortex,
often inverted; an underlying paucicellular layer; and a
large rim of ectopic small neurons.
included 16 patients with lissencephaly type 1, the cortex
was always thick, but the degree of involvement varied
from patient to patient. The brains with LIS1 mutations
had the classic four-layer cortex, but patients with DCX
and ARX mutations had different and distinct cytoarchi-
tectural findings.
116
115
In another study that
112
114
Chapter 7 Malformations of Cortical Development
265
A
AC
C
Figure 7–18. Focal unilateral parietal agyria with periventricular heterotopia in a fetus at 40 postmenstrual weeks referred for evaluation of a large
interhemispheric arachnoid cyst. (A) Nonorthogonal view of the affected side shows irregular ventricular wall with abnormal brain tissue bulging into
the ventricle ( arrow ). (B) Coronal view at the level of the third ventricle shows the irregular ventricular wall ( arrows ); note the lack of normal sulci on the
affected side. ( C) Axial MRI demonstrates the periventricular heterotopia ( arrow ), with the pachygyric overlying cortex ( arrowhead ) and the posterior
interhemispheric arachnoid cyst (AC). (D) Macroscopic pathology confirms the presence of heterotopia ( arrow ) and pachygyria ( arrowhead ).
In brains with SBH, the outer cortex is normal with
heterotopic, mainly pyramidal, neurons present in the
deeper cortical layers and in the white matter.
117
Associated Anomalies
Children with lissencephaly have profound mental retardation. Isolated LIS1 usually is not accompanied by any
associated malformations.
In MDS the lissencephaly is always severe. Associated
brain anomalies include dysgenesis of the corpus callosum
and large cavum septi pellucidi. Some patients have an
unusual midline calcification in the region of the corpus
callosum or septum; the cerebellum is not affected.
B
D
Sonographic Diagnosis
The prenatal diagnosis of MDS may be possible, especially in patients known to be at risk of recurrence
or when a possible diagnosis is suspected during a US
examination.
on the recognition of abnormal sulcation patterns, but the
differentiation between normal and abnormal sulcation may
be difficult particularly during the second trimester
Figure 7–19 ).
(
Saltzman et al
tal diagnoses of MDS. In one case, there was a prior child
with lissencephaly, agenesis of the corpus callosum, right
114
118 , 120 , 121
Diagnosis in low-risk patients depends
118
reported in 1991 the first two prena-
118 , 119
122 – 124
Microcephaly is characteristically not present at birth but
develops during the first year of life. Non-CNS changes
include the face with prominent forehead, bitemporal hollowing, short nose with upturned nares, protuberant upper
lip, thin vermilion border of the upper lip, and small jaw.
114
Some common findings amenable to prenatal diagnosis are
cardiac malformations (20 – 25%), genital anomalies in males
(70%), finger malformations (40 – 45%) (OMIM 247200) and
Miller-Dieker lissencephaly syndrome (MDLS). Growth
retardation and the presence of hydramnios have been retrospectively described in affected patients.
A
B
Patients with RELN mutations usually have severe
cerebellar hypoplasia and may be differentiated from other
types of lissencephaly by the prenatal development of
microcephaly.
Risk of Recurrence
In isolated LIS1 and in 80% of the patients with MDS,
the disease is caused by de novo mutations; thus, the
recurrence risk is ~1%. Parental balanced chromosomal
rearrangements and postzygotic mosaicism may be present in patients with MDS or DCX-ARX, respectively.
Figure 7–19. Abdominal transventricular axial planes in a fetus at 27
postmenstrual weeks with postnatal diagnosis of Miller-Dieker syndrome
(MDS) ( A ) and in a normal fetus of the same gestational age ( B ). The
arrows show the difference in shape between the parieto-occipital fissures and the well-developed temporal sulci forming the insula in B, and
the shallow sylvian fissure resembling a fetus at 18 to 20 weeks’ gestation
in A. Note the borderline normal size of the lateral ventricle in the fetus
with MDS.
266
Chapter 7 Malformations of Cortical Development
A
CD
Figure 7–20. Lissencephaly with cerebellar hypoplasia at 28 postmenstrual weeks. (A) The transverse cerebellar diameter is well below the fifth per-
centile. Median ( B ) and coronal ( C, D ) planes showing the lack of sulcation. Note the abnormal shape and small size of the cerebellum ( D ).
polycystic kidney, pulmonic stenosis, and a malrotated
gut. The mother had a balanced translocation affecting
chromosome 17p. The fetal karyotype was 46del(17)(13)
mat. Hydramnios was present from 25 postmenstrual
weeks, and a smooth cortical pattern was observed at
31 weeks ’ gestation. MDS was confirmed after delivery.
The second patient diagnosed at 31 postmenstrual weeks
B
fissures starting from 24 postmenstrual weeks should raise
suspicion and prompt a detailed neurosonographic examination of the brain ( Figure 7–19 ).
The detection of associated anomalies, particularly
agenesis of corpus callosum (ACC), vermian hypoplasia,
and abnormal male genitalia, helps in confirming suspi-
Figures 7–4 and 7–20 ).
cions (
had hydramnios, tetralogy of Fallot, and slightly small HC;
the fetus was also slightly small for gestational age, and
the sulci appeared smooth and underdeveloped. MDS was
confirmed with fetal blood sampling.
The sonographic diagnosis of lissencephaly relies
on the demonstration of an abnormal sulcation pattern.
As shown in a retrospective study, fetuses with MDS
had abnormal parieto-occipital and Sylvian fissures by
the time of the second-trimester US examination.
120
The
authors reported the ultrasonographic findings in a group
of seven patients with postnatal cytogenetic diagnosis of
lissencephaly associated with MDS; in six fetuses, mild
ventriculomegaly was present at the time of the first US
examination performed between 20 and 33 weeks ’ gestation, and a prenatal diagnosis of MCD was obtained in
three fetuses with the additional use of MRI.
120
During fetal life and even after termination of preg-
MRI Diagnosis
In adults and children, MRI is the method of choice for
the detection of all MCD, specifically for the detection of
lissencephaly. This is probably also true in the fetus, but
interpretation should be by individuals experienced in fetal
neurologic imaging with MRI and familiar with fetal brain
development.
In reported cases, the patients were usually referred
for brain MRI due to the visualization of ventriculomegaly or abnormal sulcation. MRI clearly depicts the
smooth abnormal brain surface with abnormal operculization and thick cortex (
anomalies including dysgenesis of the corpus callosum,
and abnormal cerebellum and brainstem are also clearly
visualized.
19 , 120 , 126
Figure 7–21 ). Associated
nancy, a specific diagnosis in these cases may be very
difficult or even impossible without the use of molecular
biology tests. In one of the first reports of MCD, Greco
125
reported a fetus with apparently isolated lissenceph-
et al
aly that was studied using prenatal US and prenatal and
postnatal MRI, but when reviewing the images, the findings are more characteristic of hemimegalencephaly than
of lissencephaly. In our experience, we were not able, even
following autopsy, to reach a specific definitive diagnosis in
the majority of our 23 patients with MCD.
77
Sulcal development should be assessed in any fetus
with mild ventricular enlargement as that may be the
initial indicator of disruptions of cortical development.
Failure to visualize normal sylvian and parieto-occipital
Implications for Sonographic Screening,
Including Earliest Recognition
As demonstrated by Toi et al,
124
the visualization of the
parieto-occipital and sylvian fissures during the secondtrimester US examination is feasible and potentially effective as a screening method to diagnose lissencephaly. The
effectiveness of such an approach remains to be determined in the screening of a low-risk population.
Implications for Targeted Examination
The diagnosis of lissencephaly should be possible when
performing a targeted examination, but it may depend
Chapter 7 Malformations of Cortical Development
ABC
267
Figure 7–21.
agyria and multiple malformations. At 22 weeks of gestation, the sylvian fissure is absent, and the shape of the brain is abnormal, but only at 25 weeks
is the abnormal sulcation evident.
on the choice of the correct timing and on the severity
of the disease and requires familiarity with normal brain
and sulcal appearances at different gestational ages (see
Chapter 2 ).
In suspicious cases it is helpful to compare the
obtained images with these of a known normal fetus of a
similar gestational age at the same plane
Even in patients at risk due to a history of pachygyria/agyria
in two previous pregnancies, we have found it extremely
difficult to reach a decision before 24 to 25 weeks of pregnancy 77 ( Figure 7–22 ).
Detailed neurosonographic evaluation and follow-up
repeated examinations during the third trimester should
be considered in patients with non-CNS anomalies and/or
hydramnios in association with mild ventriculomegaly,
and there should be consideration for MRI examination in
a center with fetal CNS MRI experience.
Autosomal recessive lissencephaly at 22 ( A, B ) and 25 ( C, D ) postmenstrual weeks of gestation. Two previous children were born with
Prognosis
Most patients exhibit moderate to severe developmental
cephaly is characterized by profound mental retardation
and seizures that are often intractable. Patients with MDS
122 – 124
( Figure 7–19 ).
are the most severely affected and they usually die during
the first years of life.
X-linked lissencephaly and XLAG in males have a
similar prognosis. Females with SBH may present with
epilepsy, developing during the second and third decades;
some of them may be asymptomatic with normal MRI.
Obstetric Management
127
In cases with a prenatal diagnosis, termination of pregnancy should be considered.
Cobblestone Complex Syndromes
Synonyms
Lissencephaly type II, α-dystroglycanopathies, WalkerWarburg syndrome (WWS), Chemke syndrome, hydrocephaly-agyria-retinal dysplasia +/ – encephalocele
(HARD-E) syndrome, congenital muscular dystrophy
(CMD).
AB
Figure 7–22. Lissencephaly at 33 postmenstrual weeks. Transabdominal
US ( A ) and MRI ( B ) axial planes show the lack of sulcation colpocephaly
with thick cortex and mild ventriculomegaly. Note the “figure eight”
configuration in the MRI.
Definition
The cobblestone complex syndromes (CCS) are characterized by abnormal migration of the neurons through the
pia and into the meninges (overmigration) resulting in the
“cobblestone” appearance of the cortex. The cellular layers
of the cortex do not develop normally and heterotopic tissue is found between the white matter and the pia.
In this chapter, we will refer to the most common
CCS, the Walker-Warburg syndrome (WWS), which is
the most severe phenotypic manifestation of cobblestone
cortex. Other syndromes associated with cobblestone lissencephaly are Fukuyama congenital muscular dystrophy
and muscle-eye-brain disease.
268
Chapter 7 Malformations of Cortical Development
Incidence/Prevalence
WWS is a rare disease with a worldwide distribution;
however, the overall incidence is unknown.
northeastern Italy reported an incidence rate of 1.2 per
100,000 live births.
129
One study has shown that 0.7% of the
Ashkenazi Jews in Israel are carriers of a similar mutation
at the Fukuyama congenital muscular dystrophy (FCMD)
130
locus.
128
A survey in
Pathogenesis
In these patients, normal neuronal migration is not
stopped at the pial surface of the brain and overmigrates
and invades the subarachnoid space, where surface brain
vessels are enveloped. This results in a brain surface that is
predominantly smooth with very subtle nodularity (called
cobblestone cortex) and the characteristic finding of vessels that are partly buried in the brain surface.
At a molecular level, the data strongly support the
hypothesis that defects in dystroglycan are central of structural and functional brain abnormalities seen in CMD.
130
A transmembrane glycoprotein, α-dystroglycan, interacts
with several extracellular matrix components in the basal
membrane, and disruption of its function is thought to
underlie the severe defects in different tissues, including
muscle, eye, and brain development in WWS patients.
131
In mice, brain-selective deletion of dystroglycan is
sufficient to cause CMD-like brain malformations, including disarray of cerebral cortical layering, fusion of cerebral
hemispheres and cerebellar folia, and aberrant migration
of granule cells. Additionally, high-affinity binding to laminin is lost, and there are discontinuities in the pial surface
basal lamina (glia limitans) that probably underlie the neuronal migration errors.
132
Etiology
WWS is a genetically heterogeneous autosomal recessive disease characterized by congenital muscular dystrophy, cobblestone lissencephaly, and ocular malformations.
Mutations in six genes involved in the glycosylation of
α-dystroglycan ( POMT1, POMT2, POMGNT1, FCMD,
FKRP, and LARGE ) have been identified in WWS patients,
but these α-dystroglycanopathy genes are associated with
extremely variable phenotypes ranging from mild CMD to
WWS.
In a study of 43 WWS patients, Manzini et al
130
found
that 40% of them had mutations of POMT1, POMT2, FCMD,
and FKRP. In a population-based study that included all the
Italian patients with CMD, homozygous and compound
heterozygous mutations were detected in a total of 43 of
81 patients (53%) and included 7 novel variants. Mutations
in POMT1 were the most prevalent in this cohort (21%), fol-
lowed by POMT2 (11%), POMGnT1 (10%), and FKRP (9%).
One patient carried two heterozygous mutations in fukutin,
and one harbored a new homozygous variant in LARGE.
133
Pathology
The macroscopic hallmark of the brain in WWS is the
presence of lissencephaly with a very fine, “pebbly” surface
with partly buried cerebral surface vessels in association
with ventriculomegaly, thick meninges, and cerebellar
anomalies.
The pathognomonic feature of cobblestone lissencephaly is represented by pial barrier disruption with neuronal
and glial migration into the leptomeninges (
Figure 7–23 ).
This finding was observed as early as 18 to 20 weeks.
Cerebral and cerebellar cortical disorganization occur in
parallel with pial barrier disruption.
135
At 34 weeks, the
border between meningeal and neural structures becomes
harder to discern; the leptomeninges are invaded by ectopic neuroglial cells and appear richly cellular; in addition,
they become highly vascularized.
Muscular and retinal involvements are also common
in these patients (
Figure 7–23 ).
135
Associated Anomalies
According to Dobyns et al,
sistently present with cobblestone lissencephaly, pontocerebellar and retinal malformations, and CMD. CNS
anomalies including ventricular dilation with or without
hydrocephaly, macrocephaly, Dandy-Walker malformation, and cephaloceles are also relatively common. NonCNS anomalies include anterior chamber malformations,
microphthalmia, ocular colobomas, congenital cataracts,
cleft lip and palate, and genital anomalies in males.
study on a cohort of patients with “dystroglycanopathies,”
Clement and colleagues
had no or minimal brain involvement on MRI studies,
4 patients had only cerebellar involvement, and 15 had
different kinds of MCD. Only 2 had WSS, but 23 had
abnormal cognitive development. This combination of
findings with WWS has been described under the acronym HARD +/ – E (hydrocephaly, agyria, retinal dysplasia
+/ – encephalocele).
136
patients with WWS con-
137
found that 8 out of 27 patients
Risk of Recurrence
WWS is an autosomal recessive disease with a 25% risk of
recurrence in families with an affected sibling.
Sonographic Diagnosis
Prenatal diagnosis of WWS has been reported in families
138 , 139
at risk.
Crowe et al
nosis in 1985, following the postnatal diagnosis in a sibling
with hydrocephaly, bilateral microphthalmia, severe developmental retardation, and multiple brain anomalies. The
affected fetus was diagnosed at 15 postmenstrual weeks
because of the presence of a cephalocele.
Farrell et al
140
encephalocele, abnormal vermis, and retinal detachment
in a fetus from a nonconsanguinous pregnancy with recurrence in a second pregnancy. The same group reported
another case diagnosed at 37 postmenstrual weeks with
severe asymmetric hydrocephaly and signs of retinal
detachment.
141
Monteagudo et al
a patient referred at 34 postmenstrual weeks because of
ventriculomegaly; the patient was studied using TVS, thus
138
reported the first prenatal diag-
described the presence of hydrocephaly,
142
reported on the CNS findings in
136
134
In a
Chapter 7 Malformations of Cortical Development
269
A
C
Figure 7–23.
showing the unlayered cortex with neuronal invasion beneath the pia mater. (B) Neuronal invasion produces thickening of the meninges; the granular
layer is absent. (C) Muscular involvement. Note the different sizes of the muscular fibers. (D) Retinal dysplasia ( arrow ). (Courtesy of Dr. Deborah Kidron,
Kfar Saba, Israel.)
Microscopic findings in a fetus at 24 postmenstrual weeks with cobblestone complex syndrome. ( A) Low magnification slide of the brain
revealing for the first time the abnormal sulcation characteristic of WWS in conjunction with the presence of a
cephalocele, vermian agenesis, micrognathia, and left eye
cataract (
Figure 7–24 ). The presence of abnormal sulcation
may be demonstrated in patients with suspected WWS
during the third trimester but in recurrent cases the early
detection of ventriculomegaly or any other sign of CNS or
eye anomaly should suffice to establish the diagnosis
Figure 7–25 ). In low-risk patients, the same association
(
should raise the suspicion of CCS (
Figure 7–26 ).
143 , 144
In our published series of 23 patients with MCD,
we suspected the presence of WWS in 1 patient without
postnatal confirmation, and another patient with prenatal
diagnosis of lissencephaly was found at necropsy to have
77
WWS.
B
D
the few articles that compare US and MRI in a fetus with
WWS diagnosed at 20 weeks, the median images are
quite similar, demonstrating the striking brainstem kinking, severe cerebellar and vermian dysgenesis associated
with ocular changes, and small encephalocele. Brainstem
kinking or Z malformation represents abnormal persistence of the normal mesencephalic folding that is present in normal fetuses in the first trimester. The folding
normally straightens out by about 12 to 13 postmenstrual
weeks. Kinking can be demonstrated by 3D US but can
be difficult to show on 2D scans. Its persistence implies
a severe disruption of brain development and failure of
corticospinal tract development dating from the middle
of the first trimester.
147
Strigini et al
148
reported a case
with a homozygous mutation in the POMT1 gene. US
at 26 weeks showed ventriculomegaly with an abnormal
MRI Diagnosis
The prenatal diagnosis of WWS using MRI has been
described several times
believed the main asset of this MRI is its ability to analyze the posterior fossa and gyration that are not clearly
visible in sonography. But a critical review of the cited
papers is far from convincing regarding the prenatal
demonstration of cobblestone lissencephaly. In one of
145 , 146
( Figure 7–27 ). Garel 19
cerebellum; MRI added information regarding the presence of a kinked brainstem and bifid pons. US at 31 weeks
showed retinal nonattachment.
Even with the use of MRI a definitive diagnosis of
WWS may be impossible, particularly during the second
trimester, due to difficulties in the pathologic diagnosis
of CMD and eye malformations at this early stage.
highly suspicious cases, a search for putative WWS genes
may help.
148
149
In