Fetal ventriculomegaly is a common malformation
having varied etiology. How-ever, fetal ventriculomegaly in association
with vascular proliferation and diffuse calcification in CNS has been
reported in English literature only six time before(1-6). The present
paper reports a similar occurrence in a family from Indian subcontinent.
This case was slightly different from others requiring documentation
with this syndrome.
Case Report
This male neonate was the product of first pregnancy
of young, healthy, non-consangui-neous, Hindu Indian couple aged 22
(mother) and 27 (father) years. Pregnancy was under obstetric
supervision from eighth week of pregnancy. Routine obstetric ultrasound
at 16th week was normal. Pregnancy was uncomplicated until 29th week
when second obstetric ultrasound was advised for clinical suspicion of
growth restriction and oligo-hydramnios. Mother was normotensive and
without any medical or pregnancy related problems. Second ultra-sound
examination revealed mild ventriculo-megly in addition to growth
restriction and oligohydramnios and was referred to our center for
chromosomal analysis and counseling. Ultrasound examina-tion at our
center confirmed above findings. Following counseling, couple refused to
undergo invasive prenatal diagnostic proce-dure; and opted for
ultrasound follow up and early delivery. Pregnancy was followed up at
our center for next 6 weeks before induction of labour at 35th week.
Follow-up ultrasound examination showed progressive oligo-hydramnios,
growth restriction and ventri-culomegaly. Maternal serological studies (IgG
& IgM) for rubella, cytomegalovirus and toxoplasma were negative for
active infection.
A male baby weighing 900 g was born at 35 weeks. The
weight of placenta was 125 g. Apgar score at 5 minutes was 6/10.
Movements of all four limbs were seen. Examination of baby revealed
proptosis with corneal haziness on right eye, microphthalmia on left,
depressed and pulsatile anterior fontanelle, clenched hands of both side
and prominant heel of left side. Head circum-ference at birth was 24.5
cm (expected 32 cm) and crown rump length was 23.7 cm (corresponding to
27 weeks). The external genitalia were normal male. Baby was alive for
11 hours.
Necrogram was normal except for scattered
intracranial calcification. Internal examination showed dilated
ventricles and cisterns including posterior fossa cyst in CNS.
Cerebellum and vermis were hypoplastic. White caseous material was seen
on cerebral ventricular walls all over. Small and scattered white firm
areas were seen in cerebral tissue as well. No other abnormaility was
seen in thorax, abdomen and umbilical cord. The placenta was remarkably
small, however without any abnormality. Chromosomal analysis was normal
male (46, XY).
TORCH (rubella, cytomegalo virus, toxoplasma and
herpes simplex type 2 virus) analysis from cord blood sample was
negative for IgM. IgG values were 10-15% less of maternal values
indicating trans-placental transfer of maternal IgG antibodies. Brain
tissue (from caseous material) subjected to PCR analysis with primer
specific for CMV showed negative result.
Histopathological examination of brain showed
markedly thinned out cortical mantle and ill-formed gyral pattern. All
the neuronal elements appeared immature (oligodendro-glial like cells)
without any evidence of pyramidal/multipolar neurons with dendritic
branching. In addition to defects in neuronal maturation and
differentiation, there was evidence of defects in neuronal migration
(presence of clusters of small immature round neuronal cells in the deep
white matter). The cell density was low and without mitotic activity.
The cortical ribbon was infarcted and showed foci of calcification as
well as foamy histiocytes (Fig. 1). Many foamy histiocytes were
filled with calcific material. The lower part of cortex and white matter
was transversed by numerous branching vascular channels with prominent
endothelium. Wall of these capillaries were thickened and focally
hyzlinized (Fig 2).The vascular proliferation with
neovascularization and ischemic changes were focal. Islands of spotty
and flaky calcification were seen in white matter, whereas laminar
calcification was seen in cortex. Calcification was not seen in the
vessels. The leptomeninges were normal, having dilated vascular
channels, normal for the age. The leptomeninges were firmly apposed to
the pia and developing cortex.
 |
|
Fig. 1. Photomicrograph (H&E × 200) of the
cerebral cortex showing large areas of infarct containing foamy
macrophages. |
 |
|
Fig. 2. Photomicrograph (H&E × 200) of brain
section showing leash of vessels with focal thickening of the
wall. |
In white matter, many histiocytes were seen. Reactive
astrocytes were also seen along the margin of ischemia. In addition,
focal globular islands of oligodendroglial like cells were seen.
The ependymal lining of lateral ventricle showed
attenuation. The subependymal vessels were prominent, engorged and some
contained fibrin thrombi. The subependymal zone was gliotic, the
reactive gliosis was extending into basal ganglia. The
neovascularization noted in cortex was not evident close to ventricle.
Extensive calcification and vascular proli-feration
was seen in basal ganglia. Tardy neuronal maturation also was seen in
basal ganglia. No distinct inflammatory pathology or encephalitis like
feature was seen in any area. Geimsa staining was negative for
toxoplasmosis.
The vascular proliferation and calcifica-tion was
also evident in cornea, however, to a lesser extent. The other organs,
in particular liver, kidney and lungs did not show such changes. There
was no muscle (calf) hypoplasia on histo-pathologic examination.
Discussion
Fowler et al. in 1972(1) first described
hydrencephalic-hydrocephalic syndrome in five female sibs, including in
one of a pair of dizygotic twins. Pathological examination revealed
remarkable glomeruloid proliferative vasculopathy in central nervous
system (CNS) and retina. After rejecting the possibility of a congenital
infection, authors proposed an autosomal recessive genetic defect. This
report from Australia was subsequently followed by five further
publications(2-6) from Australia, Canada, UK, Spain and Belgium,
describing similar findings. Here, we describe seventh family of similar
syndrome.
Our findings, in particular that of CNS, were closely
similar to previous reports. The major findings were dilatation of
ventricles and disorganized cerebral mantle associated with vascular
proliferation and calcification throughout the CNS. Vascular
proliferation was not restricted to CNS but was also present in cornea.
In contrast to other reports, our case did not show any evidence of
arthrogryposis, pterigia, muscular hypoplasia and poly-hydramnios.
Instead, it showed severe oligohydramnios and growth restriction.
Furthermore, we observed first time in this case clinical findings like
depressed pulsatile fontanel, corneal haziness and micro-ophthalmia.
This is the third male affected conceptus among 17 cases from seven
families. Onset of pathogenesis of our case appears to be after 16
weeks. This is in accordance with Fowler et al., 1972(1).
The predominant feature of this syndrome is marked
brain immaturity. Though the brain was from 35 weeks fetus, the gyral
pattern resembled 15-16 weeks brain. The brain had partially matured as
evidenced by the formation of marginal zone (molecular layer) and
semblance of laminal cortex. In cortical ribbon many histiocytes filled
with spherules of calcification in the cytoplasm were seen suggesting
metastatic calcification. Like previous authors(2-6), we regard the
calcification as secondary occurring mainly in foci of necrosis.
Capillaries were engorged with blood suggesting venous impedance and
defective drainage. The vascular proliferation resembled a subacute
infarct in evolution in adult, indicating primary vascular pathology in
evolution. Although the vessels were prominent, there were few
functional lumens due to endothelial hypertrophy. Presence of focal
globular islands of oligodendroglial like cells in the white matter
indicates defect in migration also. The histologic features of
persistence of oligodendroglial like cells in cortex and lack of
neuronal maturation suggests that the vascular insult of defective
microcirculation had occurred in early second trimester and
neurogenesis-glio-genesis remained immature.
Absence of calcification in vascular component and
pathologic process away from outer cortex-meninges excludes possibility
of Sturge-Weber syndrome(7). Absence of distinct inflammatory pathology
or encepha-litis like features excludes possibilities of intrauterine
infection. This possibility was also excluded by appropriate
microbiological studies.
The mechanism of ventriculomegaly in this syndrome is
not clear. The progressive genesis starting from lateral ventricles
indicates that mechanism of ventricular dilatation was not due to
obstruction like aqueductal stenosis (also supported by autopsy) but
rather due to primary progressive destruction of cerebral cortex. Later,
after birth, this was again supported by findings of depressed anterior
fontanel (reduced CSF pressure). Our findings indicate that ventricular
dilatation was primarily due to failure of CNS development along with
parallel destruction of CNS due to vascular pathology.
In contrast to other reported cases, our case did not
have fetal akinesia sequence (muscle hypoplasia, less fetal movement,
arthro-gryposis, pterigia, polyhydramnios, etc.) but had extreme
oligohydramnios and growth retardation. This heterogenity could be due
to less extensive affection of anterior horn cells. Our serial
ultrasound scan indicates that pathogenetic process in our case was
maximally operative after 16 weeks and probably late second trimester to
early third trimester. This is against the views of other authors(3,4,6)
who proposed that patho-genesis starts as early as first trimester.
The importance of this proliferative vasculopathy-hydrocephaly
case report is its association with extreme oligohydramnios, growth
restriction and absence of myopathy, which has not been earlier reported
with this syndrome. This case warrants for definition of minimum
criteria for the diagnosis and it appears that polyhydramnios and muscle
hypoplasia are not essential to label this syndrome. At present it seems
a hetero-geneous entity with autosomal recessive inheritance(1,2,4,6) or
mitochondrial respi-ratory chain defect(5).
Acknowledgement
The authors thank Prof. SK Shankar, Head, Department
of Neuropathology, National Institute of Mental Health and Neuro-science’s,
Bangalore for his expert CNS histopathological evaluation. The authors
also thank Prof. S S Agarwal, ex head, Medical Genetics, SGPGIMS,
Lucknow for his critical reading of the manuscript and providing some
scientific input. Authors are grateful to Dr. Kamal Kishore, Additional
Professor, Depart-ment of Microbiology, SGPGIMS and Dr. Anju Rani,
Gynecologist, General Hospital, SGPGIMS for their role in the management
of the patient.
Contributors: AH suspected the conditon,
coordinated work-up, carried out investigations and drafted the paper;
he will act as the guarantor of the paper. IP was involved in fetal
autopsy. LP carried out histopathological examinations. She had also
coordinated cross-examination from a reputed neuropathologist (Prof. S.K.
Shankar).
Funding: None.
Competing Interests: None stated.
