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American Journal
of
Medical Genetics 17509-521 (1984)
In Utero Brain Destruction Resulting in
Collapse
of
the Fetal Skull, Microcephaly,
Scalp Rugae, and Neurologic Impairment:
The Fetal Brain Disruption Sequence
Laura J. Russell, David D. Weaver, Marilyn
J.
Bull, and Marc Weinbaum
Departments
of
Medical Genetics
(L.
J.
R,
D.
D.
W.),
Pediatrics (M.
J.B.),
and
Psychiatry (M.
W),
Indiana University School
of
Medicine, Indianapolis
Three infants are reported with a recognizable pattern of defects consisting of
severe microcephaly, overlapping sutures, prominence
of
the occipital bone,
and
scalp rugae. This condition, which we think represents microhydranencephaly,
appears to
be
produced by partial brain destruction during the second
or
third
trimester, diminution in intracranial hydrostatic pressure, and subsequent collapse
of the fetal
skull.
Several different causes for this condition have been suggested
including partial disruption of the blood supply to the brain and prenatal viral
infection.
Key words: hydranencephaly, fetal skull, disruption, microcephafy, brain destruction, scalp
ru-
gae, twins, cytornegalovirus
INTRODUCTION
Microcephaly is a relatively common problem with diverse causes and varying
degrees of severity. Here we describe a pattern of defects in three unrelated infants
characterized by severe microcephaly, rugated scalp, prominent occipital bone, over-
lapping sutures, and radiographic
or
autopsy evidence of partial brain destruction.
We hypothesize that in this condition brain growth was normal during the first
18
wk
or
so
of development with subsequent partial destruction of
the
brain followed by
reduction in intracranial hydrostatic pressure, collapse of the fetal skull, and the above
phenotype.
Received
for
publication April 18, 1983; revision received June
25,
1983.
Address reprint requests to
Dr.
David D.
Weaver,
Department
of
Medical Genetics, Indiana University
School
of
Medicine, 702 Barnhill Drive,
RR
129, Indianapolis,
IN
46223.
0
1984 Alan
R.
Liss,
Inc.
510
Russell
et
al
TABLE
I.
Maior
Manifestations
of
Patients*
Case
111
Features
Case
I
Case
I1
Age when examined (days)
17
2
1
Occipitofrontal circumference,
Brain weight, gma 33
?
68
Overlapping sutures with skull
collapse
+ +
+
Prominent occipital bone
+
+
+
Scalp rugae
+ +
+
Scalp hair pattern
N
N N
Signs of neurologic impairment
+
+
+
Intrauterine growth retardation
-
Age at death (months) 4
?
%
cm
(SD) 26.2 (-6.4)
25
(-7.5)
26 (-6.6)
Destruction of cerebral Apparently
hemispheres Marked marked Marked
-
+
*Key:
+
,
present;
-,
not present;
N,
normal;
?,
unknown.
yhe brain weight
of
normal term newborns ranges from
381
to 403 gm [Jordaan,
19791
CLINICAL
REPORTS
in Figures
1-5.
Patient
1
The patient (Fig. 1A-C) was a white female, the survivor of a twin pregnancy,
the third pregnancy for her 22-year-old mother. The mother’s first pregnancy ended
in a miscarriage while her second resulted in twin males, one
of
whom had a
meningomyelocele and the other spina bifida occulta. The mother took oral contra-
ceptives during the initial weeks of the third pregnancy. Prior to a febrile illness at
6
mo of gestation with this pregnancy, she reported that she was able to detect the
movements of two fetuses; thereafter, she felt the movements of only one.
At 36 wk of gestation sonographic evaluation of the pregnancy showed severe
microcephaly
in
the propositus. A week later the propositus and a decomposed
co-
twin were delivered. The genitalia of the co-twin appeared to be female but because
of maceration sex assignment could not made with certainty. Examination of the fetal
membranes demonstrated two sacs, each one-layer thick, indicating diamniotic mon-
ochorionic (monozygotic) twinning. The placenta, which weighed 540 gm, had
numerous areas of calcification. Microscopic examination showed areas of microin-
farction and focal calcification. The two umbilical cords were 42 and 28 cm long with
the longer one having been attached to the propositus. Both cords contained three
vessels.
An
analysis for cross circulation in the placenta was not undertaken. The
birth weight of the twins was 2,400 and
94
gm, respectively. The dead twin had
collapse
of
the skull with overriding sutures.
No
other abnormalities were detected.
We first saw our patient at
17
days, at which time her weight, length, and
occipitofrontal circumference (OFC) were 2,835 gm
(lo%),
48 cm
(lo%),
and 26.2
cm (-6.4
SD),
respectively. In addition she had overlap of the parietal and frontal
bones, prominence of the occipital bone, which rose keel-like above the rest of the
The manifestations of the three patients are summarized in Table I and depicted
Brain
Disruption
Sequence
511
Fig. l.(A-C) Case
1,
postmortem pictures,
4
mo
of
age. Note the severely microcephalic head with
ridged and overriding sutures, collapse
of
the skull, prominence
of
the occipital bone, and scalp rugae.
(Permission
to
publish
is
granted by Dr. Jan Muller and Churchill-Livingstone, Inc.)
calvaria, and curious transverse rugae
of
the scalp. These changes were also detect-
able radiographically (Figs.
1A-C, 2A,
3A).
The
scalp hair pattern was normal.
Hypertonia, hyperreflexia, a high-pitched cry, lethargy and lack.
of
visual pursuit
were also present. Serologic titers for congenital syphilis, toxoplasmosis, rubella,
cytomegalovirus
(CMV)
,
and herpes infections were not elevated. Computerized
tomography (CT scan) of the head showed hydranencephaly and an old subarachnoid
hemorrhage. The patient died at
4
mo
of
Escherichia coli bronchopneumonia. At
autopsy the
skull
sutures were fused and overlapping and entrapped the meninges.
Remnants of the cerebral hemispheres formed a bladder-like structure whose walls
were only 1-3 mm thick (Fig.
5).
The pyramids of the medulla were small due to
nearly complete absence of the pyramidal tracts; the cerebellum, leptomeninges, and
arachnoid space were normal. The total weight
of
the brain was 33 gm, approximately
1/10
of
normal. An analysis
of
the patient’s chromosomes was not done.
Patient
2
This Caucasian female was born at term to a 23-year-old
P3,
G2,
white woman
who had had no prenatal care and who smoked 1%-2 packs of cigarettes per day.
512
Russell
et
al
Fig.
2.
(A,B) Radiographs
of
skull. (A) Case
1,
again note the severe microcephaly, prominence
of
the
occipital bone, and reduced cranial height. (B) Case
3,
microcephaly, periventricular calcification,
prominence
of
the occipital bone, and collapsed calvara are seen.
Except for nausea during the first month, for which she took an unidentified medica-
tion, the pregnancy through the first 4 mo was unremarkable. However, during the
rest of the pregnancy, her weight gain was inadequate. Sonography was performed
shortly before delivery and showed oligohydramnios, microcephaly, and a fetal
thoracic diameter of
7.7
cm, the latter being consistent with 32-weeks gestation.
Delivery was uneventful. By physical assessment the patient was at a 38-week
gestation maturity level. The birth weight of 1,786 gm and birth length of 42.5 cm
were both approximately -3
SD
for 38 wk
of
gestation. The chest circumference and
OFC
at this age were
29
cm and
25
cm,
10th centile and
-7.5
SD
for gestational
age, respectively. The length age was the equivalent of 32-weeks gestation while the
OFC
for length age was approximately -3
SD.
In addition, she was noted to have
overlap of the frontal, parietal, and occipital bones, scalp rugae, and a keel-like
prominence of the occipital bone. The anterior and posterior fontanels were not
palpable.
Re
scalp
hair
pattern was normal.
Signs of neurologic impairment included
hyperactive reflexes, hypertonia, spasticity, and a high-pitched cry.
No
other abnor-
malities were noted. Serologic tests for
CMV
and herpes virus were positive at 1
:
128
and 1:160, respectively, while those of her mother for these infections were 1:128
and
1:80,
respectively.
No
follow-up titers were obtained on either the mother or the
child. Toxoplasmosis and rubella titers were
1:32
on
both individuals.
A
syphilis titer
on the mother was nonreactive. Prominence of the occipital bone and a small head
were readily discernible on skull radiographs (Fig. 3B).
A
CT scan of the head
indicated hydranencephaly with nearly total absence of the cerebrum. The infant was
discharged at 11 days. After a single visit to the emergency room for an upper
Brain
Disruption
Sequence
513
Fig.
3.(A,B)
Lateral radiographs
of
skull.
(A)
Case
I,
(B)
case
2;
note severe reduction in cranial size.
514
Russell
et
a1
Fig.
4.
occipital
bone
are apparent.
Case
1,
autopsy specimens. Lateral view
of
calvaria. Sutural ridging and prominence
of
the
respiratory infection, she was lost to follow-up; at that time (age
4
mo) her OFC was
29 cm (-9
SD).
A chromosome analysis never was performed on this patient.
The infant had two older normal sibs. The family history was otherwise
uninformative.
Patient
3
The third infant was a male born at term to a 23-year-old white mother who
suffered an influenza-like illness at about the 26th wk of gestation.
At
34-weeks
gestation fetal sonography showed a small biparietal diameter. At birth the infant was
small for gestational age with a birth weight and OFC
of
1,960 gm
(-5
SD)
and 26.0
cm (-6.6
SD),
respectively. She had overlap at the sagittal, coronal, and lambdoid
sutures, keel-like prominence of the occipital bone, and longitudinal scalp rugae.
The
scalp
hair pattern
was
normal.
Other anomalies included abnormal ears, bilateral
optic atrophy, a narrow, bell-shaped chest, splenomegaly, tapering
of
the fingers,
contractures at the ankles and elbows, and abnormal palmar creases. Neurologic
impairment was evidenced by hyperactive reflexes, an inadequate suck and seizure-
like limb movements. The CMV titer was 1:256 while the cord blood IgM was
74
mg/dl (normal 0-29 mg/dl). Mild thrombocytopenia was also present. Chromosomes
were normal. Radiographs of the skull showed pronounced intracranial calcifications
outlining the ventricles, prominence of the occipital bone and a small collapsed
calvaria (Fig. 2B). Enlargement
of
the lateral ventricles and a cerebral wall of
minimal thickness were seen in a CT scan
of
the head.
Brain
Disruption
Sequence
515
Fig.
5.
hemispheres.
Case
1,
autopsy specimens. Brain and spinal cord showing bladder-like remnants
of
the cerebral
The infant had recurrent episodes of bradycardia and cyanosis while feeding
and died suddenly on the 23rd day
of
life. At autopsy, the weight
of
the brain was
68
gm, one fifth of normal, while that
of
the spleen was three times normal. Examination
of the brain showed microgyri with cobblestone appearance
of
cerebral surface. In
addition, there was colpocephaly, periventricular calcification with focal areas of
destruction, and severe cerebellar and optic nerve hypoplasia; the olfactory tracts
were present. The aqueduct of Sylvius was patent and
the
choroid plexus appeared to
be normal. The leptomeninges were thin and delicate with a normal appearing
subarachnoid space. Histologic section
of
the brain showed extensive periventricular
calcification.
DISCUSSION
These three infants all had a disruption sequence characterized by severe
microcephaly, overlapping
of
sutures, occipital prominence, scalp rugae, signs of
neurologic impairment, and a normal scalp hair pattern. We postulate that this
516
Russell
et
a1
THE FETAL BRAIN DISRUPTION SEQUENCE
Normal Brain Development (prior
to
12
weeks1
Prenatal Viral Infection Vascular Insults Hyperthermia
(?I
Neurologic
Partial Brain Necrosis
Impairment Micrencephaly
t
Skull Collapse
-
Severe Microcephaly
Scalp Rugae
Prominent Occiput Overlapping Sutures
Fig.
6.
Proposed sequence
of
events in the fetal brain disruption sequence.
phenotype, which we have designated the fetal brain disruption sequence, is the
consequence of events described below (Fig. 6). In each of the three infants, we
hypothesize that brain growth was normal during the first 12 wk or
so
of intrauterine
development. Subsequently, partial destruction of the brain occurred resulting
in
severe micrencephaly, diminished intracranial pressure, and collapse
of
the fetal skull.
The latter then led to severe microcephaly, sutural ridging, and scalp rugae. In the
following section we present evidence for this hypothesis and discuss
the
possible
causes of such brain destruction.
All
of
the basic structures of the brain are present by the end of the embryonic
period, ie, 12 wk [Jordaan, 1979; O’Rahilly and Gardner, 1975, 19791. During the
next
6
wk there is rapid neuroblastic proliferation and migration; the adult number of
neurons is largely achieved by the 18th wk [Dobbings and Sands, 19731. Subsequently,
brain size increases by cell hypertrophy, myelination, and formation of dendrites, and
remains proportional to intracranial volume and OFC [Vignaud, 19661. The latter
typically increases 1.5-fold between the
loth
and lgth wk. During this same period the
scalp hair pattern is established, apparently being determined by the rate of regional
brain and calvarial expansion [Smith and Gong, 19741. When brain growth is abnor-
mal before or during the 10th to 18th wk, the scalp hair pattern usually is altered
[Smith and Gong, 19731. In a study
of
severely microcephalic patients, Smith and
Gong [1974] found that 85% of these individuals had scalp hair pattern abnormalities
which they thought indicated early maldevelopment of the brain [Smith and Gong,
19731. Thus the normal scalp hair pattern in the patients presented here suggests that
brain development was normal through at least the first I8 wk of gestation.
Brain Disruption
Sequence 517
The CNS findings of the patients presented in this report bear many similarities
to those with hydranencephaly
.
This condition represents a group of disorders which
vary greatly in the presumptive time of onset, mechanism
of
pathogenesis, and regions
of brain involvement [Potter and Craig, 1975; Halsy et al, 19771 but which are best
characterized by a marked reduction in brain substance with intracranial fluid replace-
ment. Since the brains of the patients
in
this report are characterized by a
loss
of
brain mass and fluid replacement, we conclude that they had a form
of
hydranen-
cephdy. However, they differ in having severe rnicrocephaly due to collapse
of
the
skull. In the usual case of hydranencephaly there
is
a normal sized cranium. However,
a few individuals with microcephaly have been described. The French pathologist
Cruveilhier first reported this association in
1836
[Cruveilhier, 1829-18381. In his
report of an 18-month-old severely microcephalic infant with “hydrocephalic anen-
cephaly,” the physical changes were similar to those in patients presented here and
included posterior wrinkling of the scalp, prominence
of
the occipital bone, neuro-
logic impairment, and a small brain. In 1958, Crome and Sylvester reported three
cases of hydranencephaly, one of whom appears to have the same disorder described
in this paper. That female infant was born after an uncomplicated pregnancy. She had
severe microcephaly (OFC was 27 cm at 6
mo)
with ridging of the sagittal and
lambdoid sutures, and looseness and transverse folding
of
the scalp. The presence
of
neurological deficiencies was indicated by a high-pitched cry, generalized seizures,
and severe developmental delay. Death occurred at
16
mo. At autopsy the brain
weighed only 116 gm; the cerebral hemispheres consisted of fluid-filled sacs enclosed
by a paper-thin membrane. The arachnoid was fibrotic and deficient, and the aqueduct
of Sylvius was dilated. Another case was described by Muir
[
19591. The patient was
a 9-day-old Chinese female with an OFC of 29.8 (-3.5 SD). She lacked the scalp
wrinkles and sutural ridging seen in the previously described cases. At autopsy there
was hydranencephaly with preservation of
the
choroid plexus and the aqueduct
of
Sylvius
,
but obliteration of the subarachnoid space.
Collapse of the fetal skull probably occurs as the result
of
diminished intracran-
ial pressure. The latter, in turn, is most likely determined by imbalance between
production and absorption
of
the cerebrospinal fluid (CSF). Recent evidence indicates
that a substantial proportion of
the
CSF, perhaps as much as
60%
in the adult, is
produced by cells in
or
surrounding the subarachnoid space [Warkany, 197
1
;
MiIhorat
et al, 19711. This proportion may be higher in the fetus since the cells of the
embryonic choroid plexus appear to be too immature for CSF production before 8-
weeks gestation [Osaka et al, 19801. Before this time CSF appears to be produced in
the subarachnoid space and perhaps by periventricular cerebral cells.
Of 52 cases of hydranencephaly reviewed from the literature, only
17
had both
accurate OFC measurement and adequate pathologic description of the choroid plexus,
aqueduct of Sylvius, and subarachnoid space. Two
of
these had microcephaly and
were discussed above. [Crome and Sylvester, 1958; Muir, 19591; these two cases had
dilatation of the aqueduct
of
Sylvius, obliteration of the subarachnoid space and
preservation
of
the choroid plexus. Twelve
of
the seventeen had macrocephaly;
8
of
these, and all
3
normocephalic cases, had obliteration or stenosis’ of the aqueduct
of
Sylvius.
The data from our patients and those collected from the literature do not allow
insight into the mechanism producing the decreased intracranial pressure that results
518
Russell
et
a1
in the collapse of the skull. We speculate that it is owing to decreased production of
CSF relative to normal absorption. To attempt to answer why the skull collapse
occurs, we urge detailed pathologic examination and reporting of future cases.
It is likely that more than one mechanism produces the fetal brain disruption
sequence. One mechanism, as suggested from observations in patients with hydranen-
cephaly, is the interruption of the blood supply to selected areas of the brain. The
brains of persons with hydranencephaly frequently have sparing of the inferior
temporal and occipital regions, suggesting that the blood supply from the internal
carotid arteries was interrupted sometime during intrauterine existence [Halsey et al,
1977; Muir, 19591. Several animal studies offer support for a vascular pathogenesis.
Becker [1949] occluded the carotid arteries of newborn puppies by injecting the
arteries with paraffin balls. The resulting brain defects were similar to those found in
hydranencephaly
.
By ligating the common carotid arteries and jugular veins, Myers
[
19691 also was able to produce hydranencephaly in fetal monkeys. When ligation
was performed before the last third of pregnancy, a condition closely resembling
hydranencephaly in humans was produced. In those animals having larger areas of
infarction with tissue collapse and scarring, there was reduction in the volume and
height of the skull, and prominence of the occipital bone, a pattern similar to the one
described in the infants reported here.
In humans, several investigators [Benirschke and Driscol, 1967; Durlun et al,
1976; Schinzel et al, 1979; Yoshioka et al, 19791 have suggested that structural defects
may arise in utero from vascular disruptions due to a dead monozygotic co-twin.
Areas of ischemia and tissue destruction are believed to result when clots or detritus
from the dead twin embolize the circulation of the living twin via vascular intercon-
nections within conjoined placentas. Or, throniboplastin from the dead twin enters the
circulation of the living twin
in
a similar manner, inducing disseminated intravascular
coagulation and, ultimately, structural defects in the surviving twin. Hydranencephaly
is thought to arise in some cases by this mechanism [Schinzel et al, 19791. It is our
contention that one or both of the above mechanisms produced the brain defect in
case
1
of this report.
Prenatal viral infection is another mechanism thought to produce hydranen-
cephaly and, we think, the fetal brain disruption sequence. In 1964, Young and Cordy
reported injecting pregnant ewes with bluetongue virus vaccine;
20
to
30%
of the
lambs born to these ewes had either hydranencephaly or subcortical cysts. In 1971
Osburn et al, again using fetal lambs, induced hydranencephaly by direct fetal
intramuscular injection
of
bluetongue virus. All lambs infected during the second
trimester developed severe necrotizing encephalopathy, which presented as hydranen-
cephaly at birth. CMV and toxoplasmosis infections are also thought to cause reduc-
tion of brain volume by destruction of the periventricular tissue leading to passive
enlargement of the ventricles [Halsey et al, 19771. Disseminated intravascular coag-
ulation and vasculitis resulting from infections with these agents may also cause
cerebral hypoxia and microinfarcts in the brain [Kurent and Sever, 19751. Since it
appears that the third patient described here had a prenatally acquired CMV infection,
we postulate that this infection produced the brain destruction found in him.
Hyperthermia is a third mechanism capable of producing a major disturbance in
brain development. Edwards
[
19691 produced micrencephaly
in
fetal guinea pigs by
subjecting their mothers
to
hyperthermia for
I
hr on
4
or
8
consecutive days during
the first half of pregnancy. Pregnant ewes who were subjected to hyperthermia for 9
Brain Disruption Sequence
519
hr daily during the last 2/3 of pregnancy had a high proportion of lambs displaying
brain cavitation [Hartley et al, 19741. Since extensive brain cavitation is similar to
hydranencephaly, hyperthermia may be capable of producing both hydranencephaly
and the fetal brain disruption sequence. In humans, Smith et
al
[1978] have shown
that relatively short periods of hyperthermia may be detrimental to brain development.
These authors found several children with cerebral dysgenesis among the offspring
of
mothers who experienced hyperthermia during their pregnancies. However, we have
no evidence at this time that hyperthermia produced the CNS destruction in any of
the infants presented here.
The brain disruption sequence described in this paper appears to be distinct
from the brain lesion reported by Garcia and Duncan [1978]. Their patient had
atelecephaly which, they suggested, resulted from interruption of normal brain
embryogenesis around the fifth week of development.
The scalp findings in the patients reported in this paper are similar to those seen
in patients with cutis verticis gyrata (CVG), a condition in which the scalp has vertical
folds, often resembling the gyri of the brain [Akesson, 1964; Berg and Windrath-
Scott, 1962; Polan and Butterworth, 19521. In contrast to the condition reported here,
CVG typically has its onset after puberty, is not associated with collapse of the
calvaria (although microcephaly may be present) and is seen primarily in association
with endocrine problems. Thus, CVG appears to be an entity separate and distinct
from the fetal brain disruption sequence.
Scalp rugae have also been described previously in individuals with either severe
microcephaly [Urich, 1976; Laurence and Weeks, 197 11 or hydranencephaly [Iivan-
ainen et al, 1977; Bauer
et
al, 19771. These patients also had signs of neurologic
impairment similar to those present in the cases reported here, but they lacked the
skull deformities.
The importance of recognizing the fetal brain disruption sequence lies in its
implications for genetic counseling, since the
risk
of this disorder occurring in future
siblings probably is low. In addition, the mechanism producing the microcephaly can
be presented to the parents. Furthermore, it may be possible through avoidance of
potential teratogens, such as hyperthermia and infections, to reduce the frequency of
this disorder in general.
ACKNOWLEDGMENTS
We wish to express
our
appreciation to Dr. Mark Bevers, Dr. Deborah Radecki,
and Dr. Henry Rikkers
for
referring the three patients reported here, to Dr. Jans
Muller for assistance with the neuropathology, to Dr. William DeMyer, Dr. Bhuwan
Garg, Dr. Joe Christian, Dr. David Bider, and
Dr.
M.
E.
Hodes
for
reviewing the
manuscript,
to
Ms.
Elaine Anderson for reviewing in-patient records, and to
Ms.
Mary Lucas and
Mrs.
Karen Chisham for editorial assistance.
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