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250
Chapter 7 Malformations of Cortical Development
Table 7–2. SYNDROMES WITH POSSIBLE PRENATAL MICROCEPHALY (CONTINUED)
Earliest Reported
Diagnosis Methods of Diagnosis Associated Anomalies
Migration disorders with
associated microcephaly
Galloway-Mowat syndrome
195
(AR)
Miller-Dieker lissencephaly
syndrome (AD)
Norman-Roberts syndrome
197
(AR)
120 , 196
Metabolic diseases
3-hydroxyisobutyric
aciduria (AR)
Maternal phenylketonuria
embryopathy
198
199
Recessive hereditary
methemoglobinemia type II
200
(AR)
Smith-Lemli-Opitz
syndrome (AR)
201
Skeletal dysplasia s
Microcephalic
osteodysplastic primordial
dwarfism type I (AR)
Juberg-Hayward syndrome
204
(AR)
Seckel syndrome (AR)
202 , 203
205
Chromosomal disorders
71
Trisomy 21
Trisomy 13
Trisomy 18
5p deletion (cri du chat)
Mosaic variegated mutation
syndrome (AR)
Nijmegen breakage
syndrome (AR)
Triploidy
Wolf-Hirschhorn
syndrome
First trimester US, karyotype Increased NT, CHD
5
First trimester US, karyotype CNS, facial, CHD
5
First trimester US, karyotype CNS, facial, CHD, skeletal
206
207
208
209
First trimester Karyotype, US
210
Second trimester US, MRI IUGR, facial, MCD
Late second trimester FISH, US, MRI Lissencephaly,
Second trimester US, MRI IUGR, facial, lissencephaly
Second trimester
Third trimester
3-OHB elevated in AF
US, MRI
Second trimester US IUGR, CHD, MR
Birth Clinical presentation, low
cytb5r activity
Second trimester Low E3, elevated 7-dehydroc-
holesterol, mutation analysis,
US
Second trimester US IUGR, CNS, skeletal, CHD,
Second trimester US IUGR, CNS, facial, skeletal
Second trimester US, MRI IUGR, skeletal, facial
Second trimester US, karyotype IUGR, facial
22 weeks US, karyotype IUGR, ACC, CH, DWM, facial
First trimester DNA analysis
Second trimester FISH, US, MRI IUGR, PVPC, facial, CHD, MRI
ventriculomegaly, MR
MCD, brain calcifications, facial
IUGR
IUGR, CNS, facial, CHD, renal,
micropenis, polydactyly
facial, micropenis
ACC, agenesis of corpus callosum; AD, autosomal dominant; AR, autosomal recessive; CH, cerebellar hypoplasia; CHD, congenital heart disease; CNS,
central nervous system; DWM, Dandy-Walker malformation; FISH, fluorescent in-situ hybridization; GUT, genitourinary tract; IUGR, intrauterine
growth retardation; MCD, malformations of cortical development; MR, mental retardation; MRI, magnetic resonance imaging; NT, nuchal translucency;
OHB, hydroxybutiric acid; PVPC, periventricular pseudocyst; US, ultrasound.
Chapter 7 Malformations of Cortical Development
Associated Anomalies
The presence of associated anomalies and their identification using imaging or pathologic description is paramount
in reaching a definitive diagnosis. The anomalies present
in microcephalic individuals may be classified into three
groups: associated anomalies directly related to the small
brain (sloping forehead, apparent large ear size, and
increased amount of extra-axial cerebrospinal fluid [CSF])
Figures 7–2 and 7–3 ) or to abnormal cortical migra-
(
tion (microlissencephaly, periventricular heterotopia, and
dysgenesis of the corpus callosum) (
Figure 7–4 ), other
brain anomalies (cerebellar or brainstem dysgenesis), and
non–central nervous system (CNS) anomalies. Non-CNS
abnormalities may involve any body system.
Risk of Recurrence
Genetic counseling for families with known single-gene
defects is straightforward. The genetic counseling recommendations for primary microcephaly are not yet clearly
established. Based on the growing number of autosomal
recessive microcephaly loci being reported, Dobyns
ommends giving a 25% recurrence risk to parents of any
child with microcephaly with simplified gyral pattern or
primary microcephaly
.7
He believes that the lower risks
suggested by older studies is probably due to inclusion of
children with nonspecific mild microcephaly.
The recurrence risk may be as high as 50% when one of
the parents is microcephalic with normal intelligence,
in these cases, the child will have normal or near-normal
intelligence.
Figure 7–2. Newborn with severe microcephaly showing sloping fore-
head. The size of the ear is normal but when compared with the small
head gives the impression as being big.
rec-
20 , 21
Figure 7–3. Increased amount of subarachnoid fluid due to the pres-
ence of a very small brain in a microcephalic fetus at 24 postmenstrual
weeks. The abnormal subarachnoid space is particularly evident around
the frontal lobe ( arrow ).
Sonographic Diagnosis
The diagnosis of fetal microcephaly is mainly based on biometric measurements. An accurate diagnosis can be difficult, especially in borderline cases due to various factors,
including gestational age uncertainties; lack of appropriate
HC charts specific for gender, ethnic background, and fetal
weight; influence of parental head circumference; and late
development of microcephaly during the third trimester or
postnatal period.
22 – 25
Generally, suspicion should be aroused by any head
size that is significantly smaller than expected for dates or
in comparison to other body parts. Suspected cases should
undergo detailed evaluation of the brain and all other body
systems. Most significant cases will have additional findings beyond small head measurements, and these can help
to confirm the diagnosis. Often intracranial brain structures are very difficult to see because the cranial sutures
are very narrow (
Figure 7–5 ). This limited visibility itself
is a clue to failure of brain growth because skull growth
depends on brain growth.
Chervenak et al
6
published in 1984 a paper on the
diagnosis of fetal microcephaly. More than 25 years later,
it continues to be the main reference for calculating
abnormal HC size and counseling. According to their
data, microcephaly was diagnosed when the HC is found
to be <−3 SD. Using this cutoff, they had no false-negative
diagnoses; an HC <−4 SD was a specific cutoff without
false-positive patients. An HC/abdominal circumference ratio <3 SD and a femur length/head circumference ratio >3 SD were also helpful in the diagnosis
Chapter 3 ).
26
251
(see
252
Chapter 7 Malformations of Cortical Development
CSP
AB
CD
Figure 7–4.
corpus callosum of irregular thickness ( arrows ) with a large cavum septi pellucidi (CSP) and cavum verga (CV); the vermis is not clearly defined ( arrow-
heads ). (B) Parasagittal plane at the level of the insula shows complete lack of sulcation. (C) Coronal plane at the level of the frontal lobes showing similar
findings. Note the wide interhemispheric fissure with increased amount of cerebrospinal fluid (CSF) between the lobes ( arrows ). (D) In a more posterior
coronal plane, the CSP is abnormally large.
to improve diagnostic accuracy,
been independently verified.
A fetus with microcephaly, lissencephaly, and dysgenesis of the corpus callosum at 33 weeks, 4 days. ( A) Midsagittal plane shows a thin
Other measurements have been proposed in an effort
27 , 28
23
Patients with extreme microcephaly have been diag-
nosed as early as 15 postmenstrual weeks of pregnancy, but
CV
but these have not
CSP
this is the exception.
29
These patients usually have multiple malformations, and the diagnosis is straightforward
( Figure 7–6 ). It is of paramount importance to remember that prenatal diagnosis consistently fails to diagnose
most cases of primary microcephaly mainly because head
growth is normal until late pregnancy. In a study of 9600
low-risk pregnancies evaluated using axial planes that
included HC measurements, Reece and Goldstein
to diagnose all 5 cases with microcephaly. Bromely and
Benacerraf
31
found that 6 out of 7 microcephalic children
30
failed
had a normal HC before 22 postmenstrual weeks of pregnancy, and microcephaly was detected between 27 and 33
postmenstrual weeks of pregnancy. Even in high-risk cases
with recurrence risk of 25% to 50%, the likelihood of reaching a correct diagnosis during the last weeks of pregnancy
may be impossible.
Pilu and colleagues
23 , 32
33
reported on the prenatal diagnosis of microcephaly in two fetuses assisted by transvaginal sonography (TVS) and color Doppler. In these
two cases, TVS revealed aberrant findings, including
large subarachnoid spaces and a rudimentary shape of
the lateral ventricles. In one of these fetuses, a sloping
forehead was present; and in the other, power Doppler
ultrasound (US) demonstrated a discrepancy in the
size of the signals generated by the intracranial arteries
branching from the internal carotid arteries and those
branching from the vertebral arteries. This was inter-
Figure 7–5. Difficult visualization of the brain in a fetus at 26 postmen-
strual weeks with a small head circumference (HC <3 standard deviations
[SD]). A similar picture in a fetus with normal HC should raise the suspicion of craniosynostosis.
preted as the consequence of a reduced blood supply to
the undersized cerebral hemispheres.
33
The authors suggested that evaluation of intracranial anatomy by TVS
and power Doppler examination of the cerebral vessels
Chapter 7 Malformations of Cortical Development
AB
CD E
Figure 7–6. Discordant twin pregnancy at 18 postmenstrual weeks. Twin A, female with microcephaly, occipital encephalocele, ventriculomegaly, and
facial dysmorphism; twin B, normal male (not shown). ( A) Lemon-shaped calvarium with bilateral ventriculomegaly. Biparietal diameter (BPD) = 30 mm,
well below the fifth percentile, HC = 117 mm, between –2 and –3 SD. ( B) Ventriculomegaly with abnormal brain parenchyma and indentation of the
ventricular wall ( arrow ). ( C) F etal profile shows an abnormal nose with mild micrognathia. ( D, E) O ccipital encephalocele ( arrow ).
253
may be of value in the diagnosis of fetal microcephaly.
In fetuses with a small HC, the presence of an increased
amount of CSF surrounding the brain, particularly when
this fluid is prominent around the frontal horns and in
the interhemispheric fissure, can be an indicator of congenital microcephaly (see
Figure 7–3 ).
The accuracy of US in the diagnosis of fetal microcephaly has not been studied prospectively, but two retrospective analyses have been published. In the first study, den
Hollander et al
34
reported on 30 fetuses referred at a mean
gestational age of 27 postmenstrual weeks due to reduced
head size or suspected intrauterine growth retardation
(IUGR) or intra- or extracranial anomalies. Associated
anomalies were present in 83.3% of the patients: holoprosencephaly (16.7%), chromosomal anomalies (23.3%),
genetic syndromes (20%), and multiple anomalies (23.3%).
Only five patients were considered as representing “isolated microcephaly,” but a careful analysis of these cases
showed that three of them had other anomalies, and only
two represented patients with autosomal recessive primary
microcephaly. The authors did not describe the number of
fetuses with microcephaly diagnosed after delivery in their
34
center.
Dahlgren and Wilson
35
reviewed all cases of microcephaly diagnosed during a 10-year period at British
Columbia Women ’ s Hospital. They found 45 cases; in
21, the diagnosis was made prenatally and confirmed
postnatally. In 15 patients, the second-trimester US was
available, and 12 of these patients had a normal scan
between 15 and 20 postmenstrual weeks of gestation.
In nine patients (43%), the etiology of microcephaly
remained unclear: possible viral infection based on placental signs of villitis or chorioamnionitis (four), multiple malformations (one), constitutional (one), and no
specific etiology identified (one).
Our diagnostic approach to patients with suspected
microcephaly is presented in
Figure 7–7.
Magnetic Resonance Imaging Diagnosis
Magnetic resonance imaging (MRI) can be very helpful and
may add information regarding associated malformations
and subtle differences in the gyration pattern that may be
difficult to visualize by US. The characteristic receding
forehead, increased amount of extra-axial fluid, and presence of a simplified gyral pattern have been reported using
19 , 36
( Figure 7–8 ). It is important to remember that in
MRI
all these patients, the MRI was performed following the
measurement of an HC < – 3 SD.
Implications for Sonographic Screening,
Including Earliest Recognition
Frustratingly, most children suffering from primary microcephaly will have normal HC when examined during the
second trimester and even later on in pregnancy or at
birth. The only chance to reach a diagnosis in at least some
of the patients will be to perform follow-up examination
of those fetuses with an HC in the low-normal range, but
we doubt that such an approach is warranted. Another
possibility should be rescreening at 32 to 34 postmenstrual
weeks. Fetuses with syndromic microcephaly may be
detected during routine second-trimester US based on the
presence of associated anomalies.
Implications for Targeted Ultrasound Examination
In families at risk of microcephaly following the diagnosis of the disease in a sibling or when one of the parents has microcephaly, it is important to obtain exact
dating using first-trimester US measurements. An early
254
Chapter 7 Malformations of Cortical Development
Head Circumference < 2SD
No associated anomalies
Consanguinity, familial history
HC measurement of parents & siblings
Positive history of child with
microcephaly & MR
Recurrence risk ~ 100%
If abnormal (Lissencephaly,
simplified gyral pattern)
No history
Normal parental HC
Fetal Neurosonography
Karyotype
TORCH
If HC < 3SD:
Fetal brain MRI
Associated anomalies
Prognosis according to
syndromic diagnosis
Familial small HC
Normal intelligence
Good prognosis
Follow up every 3 wks
If normal
MR = 100%
Figure 7–7.
Figure 7–8. T2-weighted magnetic resonance imaging (MRI) at 31 postmenstrual weeks in a fetus with microcephaly and simplified cortical pat-
tern. Axial ( A ), coronal ( B ), and sagittal ( C ) planes show sloping forehead and increased extra-axial fluid with abnormal, simplified sulcation pattern.
(Courtesy of Dr. Atil Yuksel and Dr. Arda Lembet, Istanbul, Turkey.)
Proposed flowchart for the diagnosis of microcephaly.
A
B
MR risk increases with
severity of microcephaly
C
Chapter 7 Malformations of Cortical Development
255
second-trimester anatomical US examination performed
between 14 and 16 postmenstrual weeks of gestation may
be used to rule out the presence of associated anomalies. Fetal measurements should be performed at 4-week
intervals until term to evaluate the HC growth curve. A
detailed neurosonogram or MRI is indicated at around 32
postmenstrual weeks if the HC is small.
The use of gender-specific charts
37
may be helpful in
improving diagnostic accuracy.
Prognosis
The fate of fetuses with an HC between – 2 SD and – 3 SD
during pregnancy is still not clear. In a recent study,
found that when excluding fetuses with associated malformations, there were no significant differences in neurodevelopmental performance at the ages of 2 to 4 years
between children that had small HC (between – 2 SD and
– 3 SD) in the prenatal period and controls. Studies have
shown that children with an HC between – 2 SD and – 3 SD
are more likely to have learning disabilities with nearnormal intelligence.
Arvey et al
38
39
found that in children with microcephaly,
diagnosed during the first year of life, the risk of moderate
to severe mental retardation increased from 33% to 62%
when comparing children with a HC between – 2 SD and
– 3 SD and those with an HC < – 3 SD.
Outcomes in those syndromes and associated anoma-
lies can depend on the associated abnormalities.
38
we
Obstetric Management
Syndromic and autosomal recessive primary microcephalies are conditions associated with a high risk of moderate to severe mental retardation, and termination of
pregnancy, when legally possible, should be offered. Milder
cases will continue to be very difficult to manage.
Careful examination of the parents and family history
is important because some normal families have members
with small-appearing heads.
Macrocephaly
Synonyms
Macrocrania. Following exclusion of ventriculomegaly and
enlarged subarachnoidal spaces, megalencephaly, megacephaly, megalocephaly may be used as synonyms.
Definition
Macrocephaly is defined in children and adults as increased
brain weight and an HC >2 SD above the mean or above
the 98th percentile. The diagnosis excludes head enlargement that is secondary due to other causes, such as
hydrocephaly, subdural hematoma, and tumors. As in
microcephaly, the diagnosis of fetal macrocephaly may
carry a grave prognosis, but the possibility of a false-positive diagnosis should be considered. Common pitfalls may
be due to measurement errors and lack of normograms
based on fetal gender, ethnic background, and parental
HC. It should be remembered that using +2 SD as the
upper limit automatically categorizes 2% of the population
as macrocephalic. There is no consensus during fetal life
regarding the exact definition of an abnormally large HC
as there is no available literature on this issue.
32
The U.S.
Centers for Disease Control and Prevention (CDC) growth
charts for HC have recently defined the 97th percentile at
birth as 39 cm for boys and 38 cm for girls ( http://www.
cdc.gov/growthcharts/ ). These charts are not concordant
with the fetal charts.
Incidence/Prevalence
Statistical data regarding the prevalence or incidence of
macrocephaly at birth in the general population are scant.
In a study performed in Sweden only in boys, it was found
that the prevalence was 1 in 198.
rates of macrocephaly range from 1 in 1146 to 1 in 50,000.
40
In autopsy series, the
41
Macrocephaly is more prevalent in selected populations,
such as children with learning disorders, 42 developmental
disabilities,
43
or autism.
Pathogenesis
Macrocephaly is considered a defect of cell proliferation
due to either a more rapid or prolonged time of cell replication or a reduced rate of cell apoptosis. 5 Although the
total number of neurons is increased, the cells are morphologically normal.
In a mouse model, postnatal progressive megalencephaly has recently been linked to potassium channel
dysfunction. The authors propose that a potassium ion
channelopathy may be the cause of idiopathic megalencephaly and early-onset epilepsy in a group of infants or
young children with or without cognitive impairments.
44
Etiology
Macrocephaly may be isolated or part of a syndrome.
There is an isolated form known as familial benign macrocephaly which is due to enlargement of the subarachnoid
space and may be transmitted as a dominant or recessive
trait or be sporadic.
Macrocephaly associated with other malformations
is usually due to specific syndromes, some of which may
be diagnosed prenatally
45 – 69
( Table 7–3 ). Others, such as
Weaver, Sturge-Weber, Alexander, and fragile X, may not
manifest macrocephaly during fetal life.
Pathology
There are no available data regarding histopathology of
familial benign isolated macrocephaly.
Associated Anomalies
The diagnosis of associated anomalies enables differentiation between syndromic and nonsyndromic cases, and a
detailed search should be performed when macrocephaly
develops in utero. Family history is important because
about half the cases will be benign familial macrocephaly. The search for associated anomalies should be initially oriented toward differentiation between fetuses with
256
Chapter 7 Malformations of Cortical Development
Table 7–3. SYNDROMES WITH MACROCEPHALY IN WHICH PRENATAL DIAGNOSIS MAY BE POSSIBLE
Earliest Reported
Diagnosis Method References
Syndromes
45
67
47
69
48
49
50
, Nyberg et al 51
52
55
56
, Alessandri et al
58
59
61
66
62
63
PTEN-related syndromes Birth Mutation analysis Tekin et al
Neurofibromatosis type 1 27 weeks US, MRI McEwing et al
Linear epidermal nevus syndrome 30 weeks US Neis et al
Hemimegalencephaly 25 weeks
32 weeks
US
MRI
Malinger et al
Agid et al
Frontal macrocephaly, polymicrogyria 21 weeks US, MRI Parazzini et al
Macrocephaly with thick corpus callosum 23 weeks US, MRI Lerman-Sagie et al
Overgrowth syndromes
Macrocephaly, capillary malformation
31 weeks MRI, US Gripp et al
syndrome
Sotos syndrome 31 weeks US Thomas et al
Simpson-Golabi-Behemel syndrome Birth (34 weeks) Clinical presentation Yamashita et al
Benzite et al
Perlman syndrome Birth Clinical presentation Schilke et al
Megalencephaly, polymicrogyria, and
31 weeks MRI, US Gripp et al 50
hydrocephaly (MPPH) syndrome
Neuro cardio facio cutaneous syndromes
Costello syndrome 27 weeks US Lin et al
Metabolic diseases
Glutaric aciduria, type 1 (GA-1) 33 weeks US, MRI Mellerio et al
D-2-hydroxyglutaric aciduria 40 weeks US, Mutation analysis Zafeiriou et al 60
Augoustides-Savvopoulou
et al
Canavan disease Birth Clinical presentation Traeger et al
Megalencephalic leukodystrophy with
First trimester Mutation analysis Shukla et al
cysts (MLWC)
Skeletal dysplasia s
Achondroplasia 27 weeks US Huggins et al
Thanatophoric dysplasia 15 weeks
27 weeks
US
US
See Figure 7–9
Chen et al
Campomelic acampomelic dysplasia Birth (33 weeks) Clinical presentation Michel-Calemard et al
Greig cephalosyndactyly syndrome Birth Clinical presentation Sobetzko et al 65
Chromosomal disorders
46XX del [3q]26.1-27.1 20 weeks US See Figure 7–10
4 6
6 8
, Chen et al 53
54
, Hughes-
64
5 7
MRI, magnetic resonance imaging; PTEN, Phosphatase and tensin homolog; US, ultrasound.
Chapter 7 Malformations of Cortical Development
257
AB
Figure 7–9. Thanatophoric dysplasia in a fetus at 15 postmenstrual weeks. (A) Frontal bossing with an HC above the 98th percentile. (B ) Very small
and bowed humerus. (C) Abnormal temporal sulcus (normally apparent by the early third trimester).
abnormal growth (overgrowth syndromes or skeletal dysplasias) and those who only have a large HC (
Figure 7–9 ).
As with microcephaly, macrocephalic individuals display
craniofacial anomalies that may be directly related to
the large brain (frontal bossing and increased amount of
extra-axial fluid) ( Figures 7–9 and 7–10 ) or associated with
MCD (pachygyria, polymicrogyria, periventricular heterotopia, and dysgenesis of the corpus callosum) ( Figures 7–9,
7–10, and 7–11 ), other brain anomalies (ventriculomegaly
and cerebellar or brainstem dysgenesis) (
non-CNS anomalies (
Figure 7–9 ).
Figure 7–10 ), or
When searching for non-CNS anomalies, particular
attention should be given to the extremities (polydactyly
and vascular malformations)
50
( Figure 7–11 ).
may have a recurrence risk of up to 50%, but this is usually
a relatively benign condition. According to Arbour et al,
the inheritance pattern of nonsyndromic macrocephaly is
considerably lower than expected for an autosomal dominant trait and should be considered multifactorial and
not dominant. Similar findings were found in the Swedish
study previously mentioned.
Sonographic Diagnosis
Due to its development in late pregnancy or after birth,
macrocephaly is usually not diagnosed during pregnancy,
and when suspected during the third trimester, biometric
and anatomical evaluation are usually difficult. Accurate
C
40
diagnosis can be limited due to gestational age uncertain-
Risk of Recurrence
Genetic counseling for families with known single-gene
defects is straightforward. Familial isolated macrocephaly
ties, lack of appropriate gender-specific fetal HC charts,
ethnic background, weight, and influence of parental HC.
According to our experience, the vast majority of
fetuses with apparently isolated macrocephaly with HC
between 2.0 and 2.5 SD are males and most of them have a
normal HC at birth.
Exceptionally, macrocephaly may be diagnosed during
the second trimester. These patients are at increased risk
of having one of the syndromic conditions (see
7–10; Table 7–3 ). The prenatal diagnosis of familial
and
Figures 7–9
isolated benign macrocephaly may be made when there
is a family history and no associated malformations 71 , 72
(
Figure 7–12 ).
A
C
Our diagnostic approach to patients with suspected
macrocephaly is presented in
Figure 7–13.
70
BD
Figure 7–10. Macrocephaly (HC = +2 SD) in a fetus at 20 postmen-
strual weeks with chromosome 3q deletion. (A) Median section of the
brain shows dysgenesis of the corpus callosum ( arrows ). (B) Paramedian
section shows ventriculomegaly; note the irregular ventricular wall
( arrow ). ( C, D) Three-dimensional (3D) imaging of the fetal profile shows
frontal bossing ( C ) and wide open anterior fontanelle ( D ).
MRI Diagnosis
MRI may add information regarding associated malformations and subtle differences in the gyration pattern
that may be difficult to visualize by US. The characteristic frontal bossing, increased amount of extra-axial
fluid, and presence of abnormal sulcation have been
reported using MRI
patients with suspected macrocephaly, caution must be
taken because increased extra-axial fluid may give a false
impression of an abnormal oversulcation pattern (see
Figure 7–12 ).
19 , 36
( Figure 7–11 ).When evaluating
258
Chapter 7 Malformations of Cortical Development
A
B
Figure 7–11. Macrocephaly/vascular malformations syndrome. Prenatal at 32 weeks of gestation ( A ) and postnatal at 2 months of age ( B ) axial
T2-weighted MRI show an abnormally open operculum lined with an abnormal cortex (polymicrogyria) ( arrows ). (C ) Ultrasound (US) at 33 postmen-
strual weeks shows syndactyly of foot fingers 5 and 6 ( arrows ). ( D) Fetal MRI shows a hemangioma of the elbow ( arrow ).
Implications for Sonographic Screening,
Including Earliest Recognition
Most of the children with isolated macrocephaly will have
an age-appropriate HC when examined during the second
trimester and even in later pregnancy or at birth. The only
chance to reach a diagnosis in at least some of the patients
will be to perform follow-up examination of fetuses with
an HC in the high-normal range, but we doubt that such
an approach is warranted.
Syndromic macrocephaly along with associated anom-
C
D
Implications for Targeted Examination
In families at risk of having syndromic macrocephaly, it is
of paramount importance to establish accurate dating in
the first trimester. An early second-trimester anatomical
US examination performed between 14 and 16 postmenstrual weeks may be performed to rule out the presence
of associated anomalies. Fetal measurements can be performed at 4-week intervals until term to evaluate the HC
growth curve. A detailed neurosonogram or MRI may
provide additional information if the HC is large.
alies may present during routine second-trimester US.
B
A
D
C
Figure 7–12.
showing subarachnoid enlarged spaces. A subdural hematoma was suspected by neurosonography due to the presence of floating echogenic material
( arrows in A and B ). MRI shows asymmetric amounts of CSF overlying the right hemisphere with residual dural thickening ( arrow ). The father is also
macrocephalic; the child is developing normally at the age of 3 years. The subdural hematoma resolved shortly after birth.
Prenatal US ( A, B ) and MRI ( C, D ) at 32 weeks’ gestation and postnatal MRI ( E ) in a patient with apparently isolated macrocephaly
E
Apparently Isolated
Chapter 7 Malformations of Cortical Development
Head Circumference > 2SD
Search for associated anomalies
259
No history
Family with normal HC
Overgrowth
Fetal neurosonography, Fetal brain MRI,
Counseling according to
Figure 7–13. Proposed flowchart for the diagnosis of macrocephaly.
Positive history Familial large HC
Detailed physical examination
for stigmata of AD conditions
Positive
Molecular evaluation
specific diagnosis
Prognosis
The fate of fetuses with an HC between 2 and 3 SD during pregnancy is not clear. In a recent study we found that
when excluding fetuses with associated malformations,
there were no significant differences in the neurodevelopmental performance at the ages of 2 to 4 years between
children with a large HC (between 2 and 3 SD) in the prenatal period and controls.
38
A study in boys has shown that those with an HC
above 2 SD have a significantly lower intelligence level
(odds ratio, 1.32; 95% confidence interval [CI], 1.11 – 1.38),
but not mental retardation (odds ratio, 1.31; 95% CI, 0.80 –
40
Others found that the risk of mental retardation in
2.02) .
children without apparent associated malformations was
as high as 7% to 10%. 73 , 74
Obstetric Management
Syndromic macrocephalies are conditions associated with
a high risk of moderate to severe mental retardation, and
termination of pregnancy, when legally possible, should
be offered. Isolated macrocephaly, particularly in patients
Ventriculomegaly
Migration disorders
Overgrowth
Limb anomalies
Polydactyly
Cutaneous findings
Table 7–3
Negative
Usually good prognosis
Follow-up every 3 wks
If HC growth accelerates &
> 3SD usually poor prognosis
with a family history and when the HC measurement is
close to 2 SD, has a good prognosis.
Hemimegalencephaly
Hemimegalencephaly describes abnormal hamartomatous
enlargement of one hemisphere. It is regarded as an abnormality of neuronal proliferation and migration and may
be due to abnormal function of left-right organizer genes.
Most cases are sporadic with unknown etiology.
Isolated and syndromic forms are described. A group
of syndromes known as neurocutaneous syndromes
are frequently associated with hemimegalencephaly.
Neurocutaneous syndromes include epidermal nevus
syndrome, Proteus syndrome, Kippel-Tréaunay-Weber
syndrome, neurofibromatosis type 1, and tuberous sclerosis complex, among others. The cerebral findings are
similar in isolated and syndromic cases.
manifestations vary with the degree of brain abnormality and can include epilepsy, psychomotor retardation,
and contralateral hemiparesis. Hemispherectomy may be
needed for seizure control.
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The clinical