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Congenital hydrocephalus and eye abnormalities with severe developmental brain defects Warburg's syndrome.

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Congenital Hydrocephalus and Eye
Abnormdties with Severe Developmental
Brain Defects: Warburg’s Syndrome
C. Bordarier, M D , J. Aicardi, M D , and F. Goutieres, MD
Five patients are reported with Warburg’s syndrome, characterized by: (1) congenital hydrocephalus, (2) severe
neonatal neurological dysfunction, (3) abnormalities of the anterior and posterior chambers of the eyes, ( 4 )absence of
known cause, and (5) severe developmental abnormalities of cortical gyration and architectonics. Fourteen similar
published cases are reviewed. The syndrome can be diagnosed during life on the conjunction of the first four features
listed. Evidence is adduced that this syndrome is a genetically determined condition with an autosomal recessive mode
of inheritance and with a 25% recurrence risk for offspring of the parents of an affected infant.
Bordarier C, Aicardi J, Goutieres F: Congenital hydrocephalus and eye abnormalities with severe
developmental brain defects: Warburg’s syndrome. Ann Neurol 16:60-65, 1984
Descriptions have appeared in the literature of several
patients with early hydrocephalus associated with ocular abnormalities-especially retinal dysplasia and retinal detachment-and
severe developmental defects of
the central nervous system not resulting from any recognizable cause. Various names have been proposed
for this association, including those of Walker’s lissencephaly 12, 141, encephalo-ophthalmic dysplasia {9,
101, oculocerebral malformative syndrome, retinal dysplasia with hydrocephalus C111, and HARD ? E syndrome (hydrocephalus, agyria, and retinal dysplasia,
with or without encephalocele) [I, 12, 181. Warburg
(15, 161 reviewed the literature concerning retinal
nonattachment associated with hydrocephalus and reported one such patient born to consanguineous parents. She proposed that the association represented a
specific syndrome, genetically determined and transmitted as an autosomal recessive character. Pagon and
colleagues 1131 subsequently suggested the term Wurburg’s syndrome for the disorder.
We report five cases of Warburg’s syndrome, including those of two siblings, and review the pertinent literature to delineate further the clinical features of the
syndrome, emphasize the variability of its expression,
and better define its diagnostic criteria.
the age of 1 month a left microphthalmos was noted, but the
lenses and ocular fundi were said to be normal. From birth
the patient had been hypotonic, immotile, and areactive. At 5
months of age, head circumference was 5 SD above the mean
for age. The posterior fontanelle was extremely wide. The
right retina had a granulous appearance, and there was a
coloboma of the right optic disc. There was a complete retinal
detachment in the left eye. Pneumoencephalography disclosed a massive hydrocephalus with a large fourth ventricle
and a permeable aqueduct. A ventriculocardiac shunt was
inserted at the age of 5 % months and controlled the hydrocephalus. The child remained in a helpless neurological condition, however, until her death at 3 % years of age. There was
no postmortem examination.
Patient 2
A female infant was born to nonconsanguineous parents after
an uncomplicated pregnancy and delivery. Birth weight was
3,870 gm. There was no obvious hydrocephalus at birth. At
A male infant, the brother of patient 1, was born by cesarean
section two years after his sister and following an uncomplicated pregnancy. The head circumference at birth was 48
cm, and pneumoencephalography showed a massive hydrocephalus without demonstrable aqueductal stenosis. The
neurological condition was precarious from birth, with massive hypotonia and absence of the primary reflexes. A right
microphthalmos was evident. Eye examination showed a
fixed pupil bilaterally. There was a complete detachment of
the right retina, a coloboma of the left optic disc, and an
atrophic appearance of the left retina. Because of the poor
neurological status, no treatment was attempted, and the
child died at 4 months of age. Neuropathological examination showed severe abnormalities of the cortical gyri in addition to massive hydrocephalus. Over most of the hemispheral
surface, the gyri appeared abnormally small and the brain
surface had a verrucous appearance. Areas of pachygyria
From INSERM L.112 and the Clinique de Genetique Medicale,
HBpital des Enfants Malades, Paris, France.
Address reprint requests to Dr Aicardi, HBpital des Enfants
Malades, 149 rue de Skvres, 75743 Paris Cedex 15, France.
Case Reports
Patient I
Received Nov 4, 1983. Accepted for publication Dec 26, 1983.
60
were evident in both central areas (Fig 1). The cerebellum
was hypoplastic, with almost complete absence of the vermis.
The brainstem was almost cylindrical, without any clear separation between medulla, pons, and cerebral peduncles. The
meninges appeared thick, and a cystic dilatation of the
supraoptic cistern was evident. Microscopic examination
showed complete absence of lamination of the cortex, which
was penetrated by gliofibrillary bundles accompanying vessels
from the pial surface. These bundles separated the cortical
neurons into glomerular or columnar formations (Fig 2).
Around the entire periphery of the brainstem, there was a
mass of glia fused with a thickened arachnoid. As a consequence, there was no subarachnoid space. The architecture of
the cerebellum was completely distorted, the various layers
being intermingled inextricably.
Patient 3
A female infant, the third child of healthy, unrelated parents,
was born at term. Head circumference at birth was 40 cm.
Fig 1. (Patient 2.) External aspect ofthe posteriorpart of the left
hemisphere. The thinned internal aspect is rdected upward. A
PachygVric area is evident, surrounded by microgyric cortex.
Fig 2. (Patient 2.) Cerebral cortex. Glio$brilLay bundles penetrate the unlaminated cortex around vesseh and isolate glomerular
formations of abnormally oriented neurons. ( x 75.)
The infant was hypotonic and unresponsive. There was an
antimongoloid palpebral slant, hypertelorism, and retrognathia. There was limitation of the extension of the hips,
knees, and elbows. The posterior fontanelle was extremely
wide and bulging. Eye examination showed fixed pupils with
posterior synechiae of the iris. Bilateral lens opacities prevented visualization of the fundi. The infant died at the age of
8 days. Neuropathological examination revealed a complete
agyria, the origin of the Sylvian fissure being the only visible
sulcus. The cerebellar vermis was absent, resulting in a very
large fourth ventricle. The brainstem was short and undivided, and two large arachnoid cysts were present, cephalad
and caudad to the optic chiasm. O n section, multiple
heterotopias were visible under the ependyma of both lateral
ventricles. A small meningocele corresponded to the en-
Bordarier et al: Warburg’s Syndrome 61
larged posterior fontanelle. The brainstem and the cerebellum had the same microscopical appearance as in patient 2.
The subarachnoid space was completely obliterated around
the brainstem. The cerebral cortex was not examined microscopically.
Patient
4
A male infant, the first child of unrelated parents, was born
by cesarean section following an uneventful pregnancy. Head
circumference at birth was 42 cm. He had a dysmorphic
appearance, with retrognathia, pterygium coli, convex feet,
and a bilateral flexus adductus deformity of the thumb (Fig 3).
He was hypotonic and unresponsive from birth. Microphthalmos of the right eye was evident. Ophthalmological examination showed a bilateral Peters’s anomaly, posterior iridolental
synechiae, and bilateral cataracts. The fundi could not be
seen. Pneumoencehalography and positive contrast ventriculography showed massive ventricular dilatation with
aqueductal stenosis. No operation was performed, and the
infant died at the age of 2 months. Postmortem examination
showed a complete agyria. There was no microscopic examination.
Patient 5
A female infant, the first child of healthy, unrelated parents,
was in precarious neurological condition from birth, with
massive hypotonia and apneas. Head circumference was 35
cm. The left eye was microphthalmic. There were bilateral
corneal opacities, the pupils were unreactive to light, and a
left cataract was present. Computed tomography evidenced
massive dilatation of the lateral ventricles and a cystic dilatation of the fourth ventricle, with hypoplasia of the cerebellar
62 Annals of Neurology Vol 16 No 1 July 1984
Fig 3. (Patient 4.) Flexus adductus deformity of both thumbs.
hemispheres. The child died at the age of 12 days.
Neuropathological examination disclosed complete agyria
(only the interhemispheral fissure and the initial part of the
Sylvian fissure were present), agenesis of the cerebellar vermis, and a rounded brainstem without separation of medulla,
pons, or cerebral peduncles. O n section the lateral ventricles
were extremely dilated. The corpus callosum was hypoplastic, and the aqueduct was slitlike. The fourth ventricle
was open posteriorly and greatly enlarged. O n microscopic
Fig 4.(Patient 3.) Cerebellum. Complete disorganization of the
lamellae is evident, with fusion of the molecular layers and
anarchic disposition of granular cells. ( x 75.)
Table 1. Neuropathological Abnormalities
Winter
Characteristic
Walker
I141
Jezequel
Krause et al
1101
181
ChemkeetalI31
Sex
F
F
M
Hydrocephalus
Aqueductal
stenosis
Posterior fossa
cyst
+
+
+(C)
+(C)
-
+
+
-
Agyria
Occipital meningocele or
encephalocele
Agenesis of
cerebellar
vermis;
cerebeh
hypoplasia
Brainstem abnormalities
Columnar or
glomerular
disposition
of cerebral
cortex
Obliteration of
subarachnoid
space
Cerebellar
dysplasia
+
+
-
M
F
+(C) +
Pagon
et alI131
F
M
F
+(C) +(C) +
Yanoff Chan Whitley
etal
etal etal
[191
1171
t21
and
Garner Aymeand
[18]
Mattei [11
F
M
+
F
+(C)
M
-
M
+(C)
+
F
F
+(C) +
-
-
-
-
-
-
-
-
+
+ -
-
-
+
+
-
-
-
+
-
-
-
+
+
+
P
+
+
+
+
-
+ +
+ +
+
-
-
-
+
+
-
-
+
+
-
-
+
-
+
+
F = female; M = male; C
+
Present Series
1
-
+ +
+ -
-
P
+
-
-
+
+
+
+
+
+
-
+
+
-
+
- +
-
-
+
-
-
-
-
+
-
-
+
-
- +
+
-
-
+ -
-
-
-
-
+
+ +
+
+
-
+ -
-
-
-
-
+
-
-
-
+
-
-
-
-
-
-
-
-
-
-
-
-
+
-
-
-
-
-
-
- +
+
+ -
-
+
+
-
Discussion
The five patients herein described evidenced severe
neurological dysfunction existing from birth and ventricular dilatation, eye abnormalities, and other developmental defects that were lethal in a period of a few
days to 31/2 years.
The main features in our patients are tabulated in
Tables 1 and 2, together with those of fourteen previously reported cases in which both clinical and pathological evidence was available [I, 2, 3 , 8, 10, 12-14,
17- 191.
Two of the listed features have been regarded as
essential for the diagnosis of Warburg’s syndrome: (1)
the retinal dysplasia and the congenital retinal detachment usually associated with it and (2) the complete
cortical agyria with absent lamination of the cerebral
cortex, which was originally described by Walker [14}
and has been found regularly at neuropathological examination in later cases 12-4, 13, 13, 191. Whitley and
colleagues [17] consider this lack of lamination to be
the one constant feature of the syndrome and suggest
that cortical biopsy pay be used for diagnostic purposes. However, one or both of these features have not
-
-
-
examination the findings were identical to those in patient 2
(Fig 4).
5
+
- +
- =
+
+
+ -
clinically obvious at birth; P = pachygyria;
4
M
F
M
F
+(C) +(C) +(C) +
-
-
=
3
2
-
-
+
-
+
+
-
+
absent or not mentioned.
been verified in all our patients or in several reported
cases IS, 10, 13, 182. Retinal dysplasia has not been
pathologically proved in any of our patients, and even
retinal detachment has not been demonstrated in three
of them, in whom abnormalities of the pnterior segment prevented visualization of the posterior chamber;
likewise, neuropathological data are incomplete in two
of our cases. In only two brains was the typical absence
of cortical lamination verified (patients 2 and 5), and
one of these brains was not macroscopically agyric. In
the remaining two patients studied postmortem only
fragmentary data are available: patient 3 had the abnormalities of the brainstem, cerebellum, and meninges,
which were also present in patients 2 and 5 as well as in
other reported cases. The brain of patient 4 was hydrocephalic and agyric but was not microscopically examined. We believe, however, that the diagnosis of Warburg’s syndrome is reasonably certain in these patients,
because (1) the abnormalities of the meninges and posterior fossa structures are unusual and probably no less
specific than the cortical ones; (2) the random association of such uncommon features as retinal detachment
and abnormalities of the anterior segment of the type
encountered, with agyria or the other developmental
defects reported in this article would seem unlikely; (3)
this association is not explained by any known cause,
Bordarier et al: Warburg’s Syndrome 63
Table 2. Neuro-ophthalmological Abnormalities
Characteristic
Walker
(141
Krause
(101
Sex
F
Corneal
opacities
Abnormalities of
iris (hypopiasia,
posterior
synechiae,
ateactive
pupil)
Abnormal anterior chamber
+
Microphthalmos
Cataracts
Persistence
of primvitreous
Optic disc
coloboma
Retinal detachment
Retinal dysplasia
(histology)
Hypoplasia of
optic nerve
Jezequei
et al
Winter
Ayme
and
Garner
[I81
and
Mattei
[21
Whitley
et a1
[I71
Yanoff
etal
Chan
etal
[I91
Present Series
[Sl
ChemkeetalC31
Pagon
etal1131
F
M
M
F
F
M
F
F
M
M
F
M
F
F
+
+
-
+
+
+
-
+
+
--
+
+
-
-
+
+
+
-
-
+
+
-
+
+
-
+
+
-
-
+
+
+
+
-
-
+
+
+
+
+
-
+
_
_
_
-
+
+
+
_
_
-
+
-
+
+
-
+
-
+
-
-
-
+
+
+
+
-
-
- +
+ -
+
-
+
-
+
+
-
-
-
-
-
-
+
+
-
-
-
+
_
_
-
-
-
-
-
-
+
+
-
-
-
+
+
t
+
+
+
+
+
+
+
-
-
+
+
-
-
-
+
+
t
+
+
+
-
L
-
-
+
+
+
+
+
-
+
_
_
-
_
F = female; M = male; -
=
_
-
-
.
t
+
+
+
+
+
-
ill
1
2
M
-
3
4
5
F
M
F
+
+
+
+
+
-
+
-
-
+
-
-
+
-
+
+
+
+
-
-
-
absent or not mentioned
such as a recognizable intrauterine infection; and (4)
the occurrence of more than one case of this association in a sibship suggests a specific condition of possible
genetic origin.
The differences observed among our patients as well
as among reported patients are probably the result of
the intrinsic variability of the disorder, a point already
emphasized 113, 171. Pagon and colleagues 1131 have
shown that the clinical picture may vary considerably
within the same sibship. The two siblings they reported
differed both in clinical presentation and in pathological findings. One was obviously hydrocephalic from
birth, whereas the other, although he had enlarged ventricles, was microcephalic with an encephalocele. The
typical agyric cortex without lamination was found in
their first patient, bur the second had a pachygyric brain
with a four-layer cortex. Similarly, a wide difference in
the duration of survival may exist in siblings, as shown
by our patients 1 and 2. The relatively long survival of
our patient 1 also demonstrates, contrary to the statement of Whitley and co-workers 1171, that patients
with authentic cases may survive for more than a few
weeks. The variability of the disease process is also
shown by the coexistence of several types of cortical
dysplasia in the same brain. The association of microgyria and lissencephaly is not infrequent ([2,4] and
our patient 2). The ophthalmological features are no
less variable, and the abnormalities of the anterior seg64 Annals of Neurology VoI 16 No 1 July 1984
ment seem to be as frequent and suggestive as is retinal
detachment, and are mentioned in all the reports.
We believe that the criteria for the diagnosis of Warburg’s syndrome should be modified to include the
following: (1) congenital hydrocephalus or ventricular
dilatation; (2) severe neurological dysfunction present
from birth; (3) abnormalities of the eyes, unilateral or
bilateral, including defects of either the anterior or posterior chambers, especially central corneal opacities,
shallow anterior chamber, iridolental synechiae, and
retinal detachment; (4) absence of any known cause,
such as toxoplasmosis, cytomegaly, or other viral infection; and ( 5 ) severe abnormalities of cortical gyration
with or without total agyria, almost always associated
with typical developmental defects of the meninges,
brainstem, and cerebellum.
Any infant fulfilling the first four criteria should be
regarded as suffering from Warburg’s syndrome until
proved otherwise. It is difficult, however, to prove the
diagnosis during the life of the patient. Diagnosis during life by cortical biopsy at the time of a shunting
operation has been proposed {I71 but may well be
insufficient because of the frequent heterogeneity of
the cortex, which may include patches of microgyria.
The site of the cerebrospinal fluid block, and hence the
neuroradiological appearance, are of no diagnostic
value, because Warburg’s syndrome can be associated
with proved aqueductal stenosis {8, 12-14] and, as in
our cases 2, 4, and 5, with abnormalities of the posterior fossa reminiscent of Dandy-Walker syndrome, and
with basilar block. It is likely that the reported cases of
Dandy-Walker syndrome with ocular abnormalities {61
were in fact cases of Warburg’s syndrome. More important, Warburg’s syndrome has been demonstrated
in two ({8) and our patient 4), and possibly three 141,
male patients with proved aqueductal stenosis and
flexus adductus deformity of the thumbs. This association is known as a separate syndrome (the BickersAdams syndrome), with a sex-linked inheritance, that
does not include eye defects. When such defects are
present, the diagnosis is more likely Warburg’s syndrome, which implies different genetic counseling.
The diagnosis of Warburg’s syndrome has obvious
consequences for genetic counseling. Pathologically
verified cases affecting two or more siblings of both
sexes born to normal parents in four families have been
reported ({l, 3, 131 and our patients 1 and 2). Another
sibship with three affected children but without
neuropathological confirmation is on record {71, and
we know of two more families with five affected siblings (L. Toudic and F. Pouplard, personal communication, 1983). This evidence strongly suggests a genetic
origin with an autosomal recessive mode of transmission, as does the presence of parental consanguinity in
at least one 13) and probably two {I61 pedigrees. This
hypothesis seems more likely than that of an inflammatory origin, which has been proposed to account for
the pathological features of the cortex, especially for
the presence of gliofibrillary bundles along the course
of the penetrating arteries. Chan and colleagues f2) and
Evrard { 5 ] believe on morphogenetic grounds that the
neuropathological picture reflects a process of diffuse,
plurifocal ischemia of probable infectious origin operative from the third to the seventh gestational months.
From a genetic perspective these morphogenetic data
suggest the possibility of an abnormal metabolite acting
throughout this period on cortical development.
The possibility of a prenatal diagnosis can be considered for couples who have had an affected child. The
onset of developmental defects is obviously precocious, and hydrocephalus could be detected by echography in the second trimester. In the one case in
whch repeated ultrasonic examinations were performed,
however, prenatal diagnosis could not be reached {l].
References
1. Ayme S, Mattei J F HARD ( + E ) syndrome: report of a sixth
family with SUPPOR for autosomal recessive inheritance. Am J
Med Genet 141759-766, 1983
2. Chan CC, Egbert PR, Herrick MK, Urich H : Oculocerebral
malformations: a reappraisal of Walker’s “lissencephaly.” Arch
Neurol37:104-108, 1980
3. Chemke J, Czernobilsky B, Mundel G, Barishak YR: A familial
syndrome of central nervous system and ocular malformations.
Clin Genet 7:l-7, 1975
4. Darnbska M, Wisniewski K, Sher JH: Lissencephaly: two distinct
clinico-pathological types. Brain Dev 5302-310, 1983
5. Evrard P: Les malformations du systPme nervew central. In
Proceedings of the Meeting “Monaco 4,” Paris, Nestle-Guigoz,
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6. Fuhshuku N, Ohba N: Congenital retinal non-attachment associated with the Dandy-Walker syndrome. Ophthalmic Pediatr
Genet 2:2 1-26, 1983
7. Gerhard JP, Brini A, Willard D, et al: Le syndrome de dysplasie
ritinienne familiale associi B une hydrocephalie. Klin Monatsbl
Augenheilkd 172:546-548, 1978
8. Jizequel C, BeUoir D, Jehan P, et al: Hydrocephalie congenitale:
anomalie bilaterale des pouces et malformations oculaires. Ann
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9. Karlsberg RV, Green WR, Patz A: Congenital retrolental
fibroplasia. Arch Ophthalmol 89:122-123, 1973
10. Krause AC: Congenital encephalo-ophthalmic dysplasia. Arch
Ophthalmol 36:387-444, 1946
11. Laval J, Chatzinoff A: Congenital retinal detachment in microphthalmia associated with internal hydrocephalus. J Mt Sinai
HOSP22154-57, 1955
12. Pagon RA, Chandler JW,
Collie WR, et al: Hydrocephalus, agyria, retinal dysplasia, encephalocele (HARD i E) syndrome: an
autosornal recessive condition. Birth Defects 14:233-241,
1978
13. Pagon RA, Sterling KC, Milan DF, et al: Autosomal recessive
eye and brain anomalies: Warburg syndrome. J Pediatr
102:542-546, 1983
14. Walker AE: Lissencephaly. Arch Neurol Psychiatry 48:13-29,
1942
15. Warburg M: Heterogeneity of congenital retinal nonattachment, falciform fold and retinal dysplasia: a guide to genetic counselling. Hum Hered 26:137-148, 1976
16. Warburg M: Hydrocephaly, congenital retinal non-attachment
and congenital falciform fold. Am J Ophthalmol 85:88-94,
1978
17. Whitley CB, Thompson TR, Mastri AR, et al: Warburg syndrome: lethal neurodysplasia with autosomal recessive inheritance. J Pediarr 102:547-551, 1983
18. Winter RM, Garner A: Hydrocephalus, agyria, pseudoencephalocele, retinal dysplasia and anterior chamber anomalies.
J Med Genet 18:314-317, 1981
19. Yanoff M, Balian Porke L, Allman MI: Bilateral optic system
aplasia with relatively normal eyes. Arch Ophthalmol 9697101, 1978
Bordarier et al: Warburg’s Syndrome
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