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240
Chapter 6 Anomalies of Ventral Induction
Table 6–3. SYNDROMES FEATURING AGENESISOF
THE CORPUS CALLOSUM
Frequently in
Acrocallosal syndrome (AR)
Aicardi syndrome (X-linked dominant)
Andermann syndrome (AR)
Cerebro-oculo-facio-skeletal syndrome (AR)
Fryns syndrome (AR)
Marden-Walker syndrome (AR)
Meckel-Gruber syndrome (AR)
Microphtalmia—linear skin defects syndrome (X-linked
dominant)
Miller-Dieker syndrome (lissencephaly syndrome)
Neu-Laxova syndrome (AR)
Septo-optic dysplasia sequence
Walker-Warburg syndrome (X-linked dominant)
Zellweger syndrome (AR)
Occasionally in
Apert syndrome (AR)
Baller-Gerold syndrome (AR)
Callosogenital dysplasia syndrome (AR)
Coffin-Siris syndrome (AR?)
Congenital microgastria—limb reduction complex
(unknown)
Crouzon syndrome (AD)
Duplication 4p syndrome
Fetal alcohol syndrome
Fetal warfarin syndrome
FG syndrome (X-linked recessive)
Frontonasal dysplasia sequence (sporadic/AD)
Gorlin syndrome (AD)
Greig cephalopolysyndactyly syndrome (AD)
Hydrolethalus syndrome (AR, X-linked dominant)
Lens dysplasia (X-linked recessive)
Marshall-Smith syndrome (unknown)
Metabolic disorders
Oculoauricolovertebral spectrum (unknown)
Oculocerebrocutaneous syndrome (Delleman syndrome)
(unknown)
Opitz syndrome (AD, X-linked recessive)
Orofaciodigital syndrome type 1 (X-linked dominant)
Peters plus syndrome (AR)
Radial aplasia-thrombocytopenia syndrome (AR)
Rubinstein-Taybi syndrome (sporadic)
Shapiro syndrome (X-linked recessive)
Simpson-Golabi-Behmel syndrome (X-linked recessive)
Trisomy 8 syndrome
Trisomy 13 syndrome
Trisomy 18 syndrome
X-linked hydrocephaly spectrum (X-linked recessive)
XO syndrome
XXXXY syndrome (hypoplastic)
Yunis-Varon syndrome
AD, autosomal dominant; AR, autosomal recessive.
yield during routine second trimester US examinations
will remain low. Should the demonstration of a median
plane be routinely required by the governing bodies, the
diagnosis of callosal anomalies would be significantly
increased.
Associated Anomalies
The high frequency of associated malformations suggests that agenesis of the corpus callosum is frequently
part of a widespread developmental disturbance. In a
large postnatal series, CNS anomalies, including microcephaly, abnormal convolutional patterns, heterotopia,
intracranial lipomas, interhemispheric cysts, neural tube
defects (NTDs), Dandy-Walker malformation, aplasia,
and hypoplasia of the pyramidal tracts, were found in
85% of cases.
49
Among the CNS malformations that are
amenable to prenatal identification, the ones that are
most frequently encountered in conjunction with callosal anomalies are Dandy-Walker malformation, cortical
malformations, and interhemispheric cysts.
41
Systemic
anomalies, including a variety of musculoskeletal, cardiovascular, genitourinary, and gastrointestinal malformations, were found in 62% of cases.
Chromosomal anomalies are found in 20% of cases
and mostly include trisomy 18, 8, and 13.
50
Agenesis of
the corpus callosum is also a part of mendelian syndromes ( Table 6–3 ). Callosal agenesis is found in two
conditions with sex-linked dominant etiology and lethality in males: the orofaciodigital type I syndrome
Aicardi syndrome.
cleft face syndrome is also frequently associated with
agenesis of the corpus callosum.
52
Frontonasal dysplasia or median
53 – 55
This condition is
51
and
usually a sporadic disease, but a few familial cases consistent with an autosomal dominant transmission have
been described.
In antenatal series, anatomical anomalies were found
in 50% of cases.
56 , 57
34
The anomaly most frequently encountered was Dandy-Walker malformation. Cardiovascular
anomalies mainly included conotruncal malformations:
tetralogy of Fallot and a double outlet right ventricle. A
detailed list of syndromes associated with agenesis of the
corpus callosum is given in Table 6–3 .
Prognosis/Clinical Manifestations
Associated anomalies are frequently found with agenesis of
the corpus callosum, and they have a major impact on the
final outcome. Knowledge of specific syndromes is impor-
58
When a syndrome or associated malformations
tant.
are diagnosed, the prognosis is severe, and termination of
pregnancy should be considered. The worst outcomes are
found in the presence of cortical malformation and DandyWalker malformation.
Counseling couples with fetuses that have seemingly
isolated nonfamilial agenesis of the corpus callosum is
difficult. The corpus callosum is phylogenetically a recent
structure, and its absence is not lethal. Isolated agenesis of
the corpus callosum may be a completely asymptomatic
event or revealed during the course of a neurologic examination by subtle deficits, such as inability to match stimuli
59
Chapter 6 Anomalies of Ventral Induction
241
using both hands or to discriminate differences in temperature, shape, and weight in objects placed in both hands.
Persons with agenesis of the corpus callosum may
have neurologic problems, such as seizures, intellectual
impairment, and psychoses. However, these conditions are
believed to be caused by abnormalities in associated cerebral anomalies rather than in the corpus callosum per se.
In postnatal series, children with isolated agenesis of the
corpus callosum are more frequently free from neurologic
compromise.
Pediatric series are based on investigation of symptomatic individuals and are therefore presumably biased.
The experience with antenatal diagnosis thus far is limited,
but it seems more favorable than expected from postnatal
data. As an isolated finding, agenesis of the corpus callosum is associated with normal to borderline intellectual
development in most cases.
34 , 60
However, long-term studies have reported a progressive decrease in intellectual
capacity throughout the years, and most infants tend to
have significant difficulties in school.
the corpus callosum have also been linked to psychoses
and inborn errors of metabolism,
61
Abnormalities of
57
but the most frequent
62
defect encountered in these patients is global or partial
hypoplasia, which is unlikely to be identified in utero.
Management
Agenesis of the corpus callosum is associated with an
excess of both neural and extraneural malformations, as
well as with chromosomal aberrations. Antenatal identification of callosal agenesis dictates the need for a careful
survey of the entire fetal anatomy, including echocardiography, karyotype, TORCH (toxoplasmosis, other infections,
rubella, cytomegalovirus, herpes simplex virus) tests, and in
cases with apparently isolated agenesis, a fetal brain MRI.
Isolated agenesis of the corpus callosum does not require
any modification of standard obstetric management.
Recurrence Risk
The risk of recurrence depends on the underlying etiology.
In nonsyndromic cases, an empiric recurrence risk of 5%
has been suggested.
63
Agenesis of the septum pellucidum is usually associated
with other brain anomalies, including holoprosencephaly and cortical malformations,
schizencephaly being particularly frequent.
12 , 64
the association with
65
Apparently
isolated cases of agenesis of the septum pellucidum may
be due to septo-optic dysplasia or represent an isolated
anomaly. Septo-optic dysplasia, also known as de Morsier
syndrome, is a rare condition characterized by optic
nerve hypoplasia, pituitary hypoplasia, and agenesis of
the septum pellucidum. The optic nerves and chiasm
are affected by different degrees of hypoplasia, resulting
in poor vision and nystagmus. A subset of these infants
are blind, but they usually will develop a modest degree
of vision function later in life. Signs of both anterior and
posterior hypopituitarism are virtually always present.
Deficiency of growth hormone and antidiuretic hormone may result in hypopituaric dwarfism and diabetes
insipidus, respectively. Low levels of thyroid-stimulating
hormone, luteinizing hormone, and follicle-stimulating
hormone are usually present.
Associated Anomalies
Ventriculomegaly, schizencephaly, agenesis of the corpus
callosum, craniofacial anomalies, such as hypothelorism
and clefting, are often present.
Etiology
The etiology is unknown. Septo-optic dysplasia can be
caused by a mutation in the homeobox gene HESX1 or
occur because of exposure to teratogens or viral infec-
66
tions.
Most cases are sporadic; standard counseling is
that the risk of recurrence is low. Hereditary cases have
been reported that were compatible with both autosomal
recessive and autosomal dominant transmission; it is presently accepted that a genetic factor plays an important
role, at least in some cases.
67
Recurrence Risk
Standard counseling is that the risk of recurrence is low,
although a few cases suggesting mendelian transmission
have been described.
67
AGENESIS OF THE SEPTUM PELLUCIDUM
AND SEPTO-OPTIC DYSPLASIA
Definition
Agenesis of the septum pellucidum is a cerebral anomaly
that features the absence of the septum pellucidum; when
this is associated with optic nerve hypoplasia and/or hypophyseal dysfunction, the condition is known as septo-optic
dysplasia (or de Morsier syndrome). (See also chapter 2)
Embryology and Pathology
The septum pellucidum is part of the midline structures
at the level of the frontal horns of the lateral ventricles;
it is made up of two leaves separated in the fetus by a
fluid-containing cavity, the cavum septi pellucidi (CSP).
Diagnosis
Septo-optic dysplasia should be suspected when the cavum
septi pellucidi is absent in an otherwise normal brain.
Visualization of the cavum septi pellucidi is usually easy,
but demonstration of the absence may be difficult at times
and the ultrasound findings may be misleading.
frontal horns are fused on the midline. The corpus callosum is usually present, although it is frequently described
as thinned in postnatal studies. Ventriculomegaly may be
present. Multiplanar imaging is essential to demonstrate
this condition and particularly to differentiate it from
other entities (Figures 6–19) . Three-dimensional imaging
usual orthogonal planes, tomographic imaging an inversion rendering of the CSP are additional and emerging
tools to differentiate this condition from other entities
(Figure 6–20).
12,25,67–69
25
The
242
Chapter 6 Anomalies of Ventral Induction
Frontal horns
A
Figure 6–19. Agenesis of the septum pellucidum. In this case, a differential diagnosis than lobar holoprosencephaly is possible by demonstrating in
the axial plane ( A ) as well as in an anterior coronal plane ( B ) that the frontal horns are separated anteriorly, with a well-developed IHF between the
anterior hemispeheres. The demonstration of a normal corpus callosum also favors the diagnosis of agenesis of the septum pellucidum. (Reproduced,
with permission, from Tutschek B, Pilu G. Virtual reality ultrasound imaging of the normal and abnormal fetal central nervous system. Ultrasound Obstet
Gynecol. 2009 Sep;34(3):259–267.)
Differential Diagnosis
The finding of an absent cavum septi pellucidi with central
fusion and squaring of frontal horns is similar to the previously described lobar holoprosencephaly. The presence of
Frontal horns
B
C
with fusion of the frontal horns is theoretically recognizable by a standard sonographic examination performed
after 18 weeks. However, we expect that this finding will
be very subtle.
Corpus callosum
D
well-formed albeit fused frontal horns that dicaricate anteriorly and the documentation of otherwise normal cerebral
structures, including a regular corpus callosum, favor the
diagnosis of absence of the septum pellucidum versus
holoprosencephaly. After birth, a definitive diagnosis of
septo-optic hypoplasia is made by the CT or MRI demonstration of optic tract hypoplasia, endocrine evaluation,
and visual assessment. In the fetus, the differential diagnosis between SOD and isolated ASP may be attempted by
evaluation of maternal urine and serum estriol levels and
fetal blood assays for growth hormone, ACTH, and pro-
67
A specific diagnosis was made antenatally in one
lactin.
case demonstrating hypoplasia of the optic chiasms with
MR in the third trimester of pregnancy
67
(Figure 6–21).
The largest available antenatal experience has been made,
however, with sonography. Three-dimensional ultrasound
visualization and measurement of the optic chiasms and
tracts (Figure 6–21) identified 4 of 5 cases of optic tract
hypoplasia within a group of fetuses with ASP.
70–71
Implications for Sonographic Diagnosis
Although the recurrence risk is low, a familial history of
septo-optic dysplasia is an indication for a targeted sonogram. It is important to stress that only those cases with
absence of the septum pellucidum are currently amenable
to antenatal sonographic recognition. We would recommend an examination at 18 weeks, when the anterior midline structures of the brain are usually clearly visualized.
Prognosis
Many fetuses with absence of the septum pellucidum have
severe cerebral anomalies such as holoprosencephaly and
schizencephaly that are rapidly identified and carry a poor
prognosis. The main problem arises after the diagnosis of
a seemingly isolated agenesis of the septum pellucidum
that, in the majority of cases, cannot be differentiated
from SOD. Isolated agenesis of the septum pellucidum has
been identified in the fetus and had a good outcome.
outcome of individuals affected by SOD is controversial.
Visual impairment is usually present, but blindness is rare.
Hypopituitarism is amenable to medical treatment. The
developmental outcome is debated. Absence of the septum
pellucidum and optic nerve hypoplasia are associated with
an excess of cerebral palsy, mental retardation, and seizures. However, abnormal development is usually limited
to those cases with coexistent cerebral hemispheric anomalies, such as schizencephaly. Of 7 infants with isolated
septo-optic dysplasia, with no other brain abnormalities,
only one was found to have moderate cognitive and language delays.
71
Antenatal series suggests that about 25% of
fetuses with seemingly isolated ASP have septo-optic dysplasia, and the remaining are usually asymptomatic.
Although the available experience is limited, it would seem
that within this group of fetuses, visualization of a normal
optic chiasm with three-dimensional ultrasound does
not rule out with septo-optic dysplasia, but significantly
decreases the risk.
71
68
The
71,73
Implications for Sonographic Screening
The experience with the antenatal diagnosis of septo-optic
dysplasia is limited. Absence of the cavum septi pellucidi
Obstetrical Management
Standard obstetric care.
Chapter 6 Anomalies of Ventral Induction
A
B
243
C
D
E
Figure 6–20.
lateral ventricles (A); cast of the lateral ventricles obtained with three-dimensional ultrasound and inversion mode (B), tomographic images in the sagittal
(C), coronal (D), and axial planes (E). (Courtesy Ilan Timor-Tritsch and Ana Monteagudo).
Sonography of fetal agenesis of the septum pellucidum: multiplanar imaging with three-dimensional rendering of the cavity of
244
Chapter 6 Anomalies of Ventral Induction
AB C D
Figure 6–21.
one (arrows) in one fetus with septo-optic dysplasia. Three-dimensional sonograms demonstrating measurement of the posterior tracts in a normal
optic chiasm (C) compared with an hypoplastic one (D). (A, B Reproduced from Lepinard C, Coutant R, Boussion F, Loisel D, Delorme B, Biquard
F, et al. Prenatal diagnosis of absence of the septum pellucidum associated with septo-optic dysplasia. Ultrasound Obstet Gynecol. 2005 Jan;25(1):73–75.)
(C, D Reproduced from Damaj L, Bruneau B, Ferry M, Moutard ML, Garel C, Odent S, Adamsbaum C, Avni F, Tréguier C, Lazaro L: Pediatric outcome
of children with the prenatal diagnosis of isolated septal agenesis. Prenat Diagn. 2010;30(12-13):1143–1150.)
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Chapter 7
MALFORMATIONS OF CORTICAL DEVELOPMENT
Gustavo Malinger ● Ants Toi ● Liat Ben-Sira ● Tally Lerman-Sagie
KEY POINTS
1. Proliferation, neuronal migration, and organization
occur relatively late in pregnancy and do not end
until after delivery.
2. Malformations of cortical development (MCD)
may be diagnosed during fetal life; the chances for
diagnosis are better in severe cases and in those
with associated anomalies.
3. MCD assay may in same cases diagnosed by using
ultrasound. Characteristic features are shown in
Figure 7–1.
4. Even when MCD is suspected, a definitive diagnosis is
usually difficult during pregnancy.
5. In patients at risk, search systematically for signs of
MCD. Check for the size of the lateral ventricles and
the regularity of their walls; also, the presence of
abnormal underdeveloped or overdeveloped sulci.
6. When a suspicion is raised, consult with a genetician
and a pediatric neurologist. In low-risk patients,
these signs may be the only possibility for prenatal
diagnosis.
The processes of primary neurulation and ventral induction that result in the formation of the neural tube and
in the formation of the prosencephalon, respectively, are
completed by the second month of gestation.
followed by three overlapping phases of cortical development, which are under the control of numerous genes:
proliferation, migration, and organization. Stem cells at
the surface of the ventricles proliferate and divide into
glial cells and neuronal cells. The glial cells migrate to the
cortex in a very regular radial pattern, leaving a radial scaffolding along which the neurons migrate (radial migration)
to the surface. The later arriving neurons migrate in stages
through the inner layers and ultimately lie outside them
(inside out migration). Ultimately, six layers are formed.
Once the neurons arrive at the cortex, they organize local
connections. In addition to this radial migration, there is a
tangential migration of neurons to form what are believed
to be controlling tracts.
development also function in other parts of the body, so it
2
The genes that control neuronal
1
This is
is not unusual to find cerebral malformations associated
with diverse somatic manifestations, such as skeletal dysplasia as present in thanatophoric dysplasia. This normal
orderly developmental process can be disturbed by genetic,
teratogenic, and environmental conditions. Because the
cerebrum develops simultaneously with other structures,
an insult at a specific time can affect the normal development of all the structures that are vulnerable at that
time, including the eyes, face, and hindbrain. Hence the
importance of assessing all of these areas if abnormality is
suspected in any one of them. Over the past decade, the
knowledge regarding the genetics, morphology, and clinical aspects of these conditions has expanded significantly,
and new developments in this field have occurred rapidly.
Different classifications of malformations of cortical
development (MCD) have been proposed
Fundamentally, they are based on two factors: gene abnormality and timing of the first abnormal developmental
event. Final phenotypic outcomes are often more dependent on the time that an insult occurs and interferes with
normal development than its specific nature. Although
Barkovich et al ’ s
useful in clinical management, they are acknowledged to be
in evolution and will change as new information becomes
available. Sarnat ’ s
genetic and embryologic mechanisms of the different diseases. The reader is referred to Chapter 2 for information
on the normal sonographic appearance and development
of the sulci and gyri.
3
and Volpe ’ s
4
classification is more centered on the
5
classifications are particularly
3 – 5
( Table 7–1 ).
MALFORMATIONS DUE TO ABNORMAL
NEURONAL PROLIFERATION
Microcephaly
Synonym
Micrencephaly
Definition
Microcephaly means small head. More specifically, it is
intended to mean small brain (micrencephaly). In children
and adults, microcephaly is defined as low brain weight
and a small occipitofrontal head circumference (HC) >2
248
Chapter 7 Malformations of Cortical Development
28w 25w
Underdeveloped cortex Irregular ventricular walls
Signs of MCD
17w
Early abnormal
sulcation
Figure 7–1. Ultrasound signs of malformations of cortical development.
25w
Parenchymal nodules
25w
Thin and irregular cortex
26w
Closed-lip cleft
Table 7–1. MALFORMATIONS OF CORTICAL
DEVELOPMENT
Malformations due to abnormal neuronal proliferation
Microcephaly
Macrocephaly
Hemimegalencephaly
Tuberous sclerosis complex
Malformations due to abnormal neuronal migration or
organization
Lissencephaly/subcortical band heterotopia spectrum
Cobblestone complex syndromes
Heterotopia
Schizencephaly/polymicrogyria
Data from Barkovich AJ, Kuzniecky RI, Jackson GD, Guerrini R, Dobyns
WB. A developmental and genetic classification for malformations of
cortical development. Neurology. 2005;65:1873–1887; Sarnat H, Flores-
Sarnat L. Integrative classification of morphology and molecular genetics in central nervous system malformations. Amer J Med Genet.
2004;126A:386–392; Volpe JJ. Neuronal proliferation, migration, organization, and mielinization. In: Neurology of the Newborn. Philadelphia:
Saunders; 2008:51–118.
standard deviations (SDs) below the mean or below the
third percentile (see Chapter 3 ). The implications of a diagnosis of fetal microcephaly may be grave. Measurements
should be carefully obtained, and normograms used should
take into consideration fetal gender, ethnic background,
parental size, and family history. Diagnosis using – 2 SDs
as the lower limit will automatically categorize 2% of the
population inappropriately as microcephalic. Such a broad
definition obviously includes normal individuals. It is clear
that there is an inverse relationship between the HC and
the probability of associated mental retardation. Prenatally,
there is no consensus regarding the exact definition of an
abnormally small HC; some authors propose the – 2 SD
3
whereas others propose the – 3 SD cutoff.
cutoff,
the – 3 SD definition, Chervenak et al
6
showed that prena-
6 , 7
Using
tal HC measurement was sensitive for diagnosing microcephaly with no false-negatives; – 4 SD was a specific test
with no false-positive cases (see Chapter 3 ).
Incidence/Prevalence
Seto et al
Japan a significant increase in the incidence of microcephaly as reported on birth forms from 0.37 per 10,000 births to
0.86 per 10,000 when comparing two consecutive 10-year
periods between 1981 and 2000. Similar results (0.67 per
10,000 births) were found in a large Chinese study that
recorded all the cases of microcephaly in newborns and
stillborns of more than 28 weeks ’ gestation diagnosed
during the first 7 days of life.
incidence of microcephaly dropped from 0.3 per 10,000
live births to 0.1 per 10,000 when the diagnosis was made
by HC measurements instead of relying only on the clinical
impression. In 1999 in the United States, the nationwide
8
noted in a population-based study performed in
9
In a Canadian study,
10
the
Chapter 7 Malformations of Cortical Development
249
rate of microcephaly was much higher and reached 5.9 per
10,000 live births;
state showed a rate of 7 per 10,000 children under the age
of 1 year.
12
11
epidemiologic data from a single U.S.
These differences are due to the fact that in the
majority of cases, microcephaly is not present at birth but
develops by the age of 1 year. In a study published in 1977,
13
found that 1.9% of the children attending regular
Sells
classes in Seattle had an HC measurement <2 D of the
mean for age and sex, but their IQs were not significantly
different than those of the control group.
Pathogenesis
According to Rakic ’ s
layer of the lateral ventricle are the precursor of neuron
and glial cells; during early proliferative stages, these
progenitor cells start to divide symmetrically until the
ventricular zone becomes highly cellular. A reduction in
the total number of progenitor cells will cause a severe and
lethal form of microcephaly known as radial microbrain.
Decreased progenitor stem cell divisions result in microcephaly vera and reduced neuron numbers. In these cases,
the weight of the brain is reduced, but macroscopically, it
will appear almost normal.
2 , 14
studies, cells in the ependymal
5
Etiology
Microcephaly can result from many different processes,
including chromosomal abnormalities, single gene defects,
infections, and environmental effects, all of which can
impair neuronal proliferation (
may be present as an isolated finding or it may be part of
a more complex condition. Only some of these conditions
may be apparent at prenatal examination. A search in the
Online Mendelian Inheritance in Man (OMIM) database
found 548 entries for microcephaly, but only some of
Table 7–2 ). Microcephaly
these conditions are apparent in utero or in the neonatal
period. When isolated, it is termed primary microcephaly.
Autosomal recessive inheritance is described with gene
mutations involving MCPH, ASPM, CDK5RAP, or CENPJ
in some mild cases, and ALM, ARFGEF2, or RAB3GAP in
more severe cases.
3
The whole picture regarding the genetics of microcephaly is far from complete, and new genes have been
described, some of them transmitted as an X-linked trait
as MRXS9 on chromosome Xq12-q21.31
somal dominant trait with incomplete penetrance due to
microdeletions on chromosome 1q21.1
cations on chromosome 9q22.32.
15
or as an auto-
16
or microdupli-
17
It is likely that current microarray-based comparative genome hybridization
(CGH) techniques will demonstrate additional gene abnormalities that are currently undetectable using conventional
cytogenetic methods.
Pathology
The information available in the literature regarding the
pathology of microcephaly is scant. Reported cases consistently describe reduced brain weight with sulcal patterns
ranging from normal to patterns described as “simplified
gyral pattern” or microlissencephaly. The actual microscopic structure of the cortex in these cases is not clear.
An example of the cerebral histology in a fetus at 26 postmenstrual weeks with microcephaly vera published by
Evrard et al
matter without migrating neurons, and abnormal superficial cortical layers. Garel described a fetus with microlissencephaly at 26 postmenstrual weeks showing normal
myelination, cortical thickness, and neuronal differentiation with a very small number of cortical neurons and
simplified gyration.
18
showed a depleted germinal layer, white
19
Table 7–2. SYNDROMES WITH POSSIBLE PRENATAL MICROCEPHALY
Earliest Reported
Diagnosis Methods of Diagnosis Associated Anomalies
Syndromes
Cerebrooculofacioskeletal
syndrome (AR)
Cockayne syndrome
189
(AR)
Cornelia de Lange
syndrome (AD, S)
Meckel-Gruber syndrome
191
(AR)
Mowat-Wilson syndrome
195
(AD)
Neu-Laxova syndrome
193
(AR)
Warburg micro syndrome
194
(AR)
188
190
Second trimester US, DNA repair analysis Microphthalmia, CNS Skeletal
First trimester DNA analysis IUGR, brain calcifications,
First trimester US, mutation analysis IUGR, GUT, CHD, facial,
First trimester US Encephalocele, polycystic kid-
Birth US, MRI ACC, CHD, facial, megacolon,
Second trimester US IUGR, CNS, skeletal, facial
Birth Clinical presentation ACC, microphthalmia, cataracts
cataracts, skeletal
skeletal
neys, polydactyly
hypospadias.
(continued)