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Prenatal diagnosis of Walker-Warburg syndrome in three sibs

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American Journal of Medical Genetics 76:107–110 (1998)
Prenatal Diagnosis of Walker-Warburg Syndrome in
Three Sibs
B. Gasser,1* V. Lindner,1 M. Dreyfus,2 X. Feidt,3 P. Leissner,4 A. Treisser,3 and C. Stoll5
Institut de Pathologie, Strasbourg, France
Service de Gynécologie 1, Strasbourg, France
Maternité-Ecole de Sages Femmes, Strasbourg, France
Service de Gynéco-Obstétrique Obernai, Strasbourg, France
Service de Génétique Médicale, Centre Hospitalo-Universitaire, Strasbourg, France
Walker-Warburg syndrome (WWS) is an autosomal recessive condition characterized
by diffuse neurodysplasia, resulting in
brain and eye abnormalities. We report on 3
prenatally diagnosed cases of this syndrome
born to a consanguineous couple.
An ultrasonographic examination showed
hydrocephalus at the 27th week of the first
pregnancy. Amniocentesis documented a
normal male karyotype. The couple opted
for termination of the pregnancy but declined an autopsy.
Seven months later, hydrocephalus was
observed at 20 weeks of the second pregnancy. Termination of pregnancy was performed at the 22nd week. Autopsy of this
male fetus showed dilated ventricles, thin
cortex, and type II lissencephaly with microscopic evidence of chaotic architecture.
Eye examination showed retinal dysplasia.
Notwithstanding the lack of demonstrable
muscle change, the diagnosis of WalkerWarburg syndrome was made.
Ten months later, hydrocephalus was discovered in the third fetus, a female, at 13
weeks of gestation. Termination of pregnancy was performed at 20 weeks. At autopsy, brain, eye, and muscular findings
were similar to those of the previous case. In
addition, cystic changes and a stenosis of
the pyelo-ureteral junction were found in
the right kidney.
Type II lissencephaly and retinal dysplasia are characteristic of WWS. Muscular dystrophy has been pointed out as an additional abnormality in postnatal cases. By
contrast, the lack of demonstrable muscle
changes in the fetal period must be emphasized. Those cases illustrate practical prob-
*Correspondence to: Bernard Gasser, Institut de Pathologie, 1
Place de l’Hôpital, 67064 Strasbourg Cedex BP 22, France.
Received 18 December 1996; Accepted 7 October 1997
© 1998 Wiley-Liss, Inc.
lems in the ultrasound and pathologic diagnosis of WWS in the fetal period. Am. J. Med.
Genet. 76:107–110, 1998. © 1998 Wiley-Liss, Inc.
KEY WORDS: hydrocephalus; lissencephaly; retinal dysplasia; kidney
dysplasia; muscle dystrophy;
atretic cephalocele
Walker-Warburg syndrome (WWS) is a lethal autosomal recessive disorder manifested by characteristic
brain and eye malformations and congenital muscle
dystrophy [Dobyns et al., 1989; Dubowitz and Fardeau,
1995]. Three prenatally diagnosed cases of WalkerWarburg syndrome that occurred in a consanguineous
family are reported with special regards to practical
problems in the ultrasound and pathologic diagnosis of
WWS in the fetal period.
Family history dates back to 3 years ago when the
first pregnancy occurred to a 18-year-old woman and
her 19-year-old husband. They were first cousins, of
Turkish extraction. This pregnancy was uncomplicated
until the 27th week when hydrocephalus was detected
ultrasonographically (biparietal diameter [BIP]: 71
mm; head circumference [HC]: 25 cm, marked ventricular enlargement, ventricular size, and cortical
mantle thickness not available). Amniocentesis demonstrated a normal 46,XY karyotype. A termination of
pregnancy was performed upon request but autopsy
was declined by the parents.
Seven months later, ultrasound monitoring of the second pregnancy led to the diagnosis of recurrent hydrocephalus at the 20th week. At 16 weeks, BIP and HC
were, respectively, 33 mm and 13.1 cm; at 20 weeks,
BIP was 55 mm and HC was 19.3 cm; lateral ventricle
size was 14 mm, the third ventricle size was 13 mm,
cortical mantle thickness ranged from 5 to 8 mm. Abortion was subsequently induced at the 22nd week. A
Gasser et al.
normal male karyotype was documented. Autopsy
showed a male fetus whose weight and height (500 g,
crown rump length [CRL]: 18 cm) were consistent with
the gestational age. With the exception of the head and
brain, the findings were normal; no thumb malposition
was found. The fetus had mild hypertelorism, flat
bridge of nose and anteverted nostrils, long philtrum in
contrast with a small chin, mildly low-set posteriorly
angulated ears, and flat occiput. The head circumference was slightly enlarged. Atretic occipital cephalocele, hydrocephalus, and major cerebral and retinal
dysplasia were present leading to the diagnostic hypothesis of Walker-Warburg syndrome in spite of the
apparent absence of muscle changes.
In the third pregnancy, 10 months later, ultrasonographic monitoring demonstrated during the 13th
week a bilateral dilatation of lateral ventricles (BIP:
26 mm; ventricular size: 7 mm). At 15 weeks, BIP and
ventricular sizes were, respectively, 30 mm and 9 mm.
Ventricular size reached 13 mm at 17 weeks. As of the
13th week, cystic changes in the right kidney were
found and confirmed by ultrasound follow-up: right
kidney enlargement (renal circumference: 50 mm at 15
weeks) with cysts of varying size and renal pelvis distention (8 mm at 15 weeks, 14 mm at 17 weeks). The
left kidney was normal. Neither ocular anomaly nor
skull defect could be demonstrated. The diagnosis of
Walker-Warburg syndrome was considered again. Despite the normality of the left kidney, a diagnosis of a
variant of Meckel syndrome was debated, taking into
account the presence in the preceding sib of an equivalent of meningocele and the present occurrence of kidney cystic changes. Termination of pregnancy was performed during the 20th week, and this third female sib
(weight: 348 g; CRL: 16 cm) showed head and brain
defects similar to those found in the previous case, i.e.,
occipital bone defect, hydrocephalus, and major cerebral and retinal dysplasia.
Shortly after termination, placenta and fetus were
fixed for a week in 10% aqueous solution of phosphatebuffered formalin. The brain was fixed for another 10
days after removal. Following gross examination, paraffin sections were stained with hematoxylin and eosin.
Both the second and the third sib demonstrated similar skull, brain, and eye anomalies. A 3-mm bone defect
was present in the upper part of the occipital bone
without demonstrable meningocele or encephalocele
(Fig. 1). In both sibs, there was marked enlargement of
the lateral ventricles (Fig. 2) with irregular thinning of
surrounding brain tissue and leptomeningeal irregularities running alongside the whole brain surface. Adhesion without cortical joining could be seen between
the frontal lobes. The corpus callosum was present. The
cortical surface appeared totally smooth except for the
Sylvian fissure which appeared abnormally flat for the
age. However, it should be noted that smoothness of
the external brain surface is a normal finding until
about the 22nd–23rd gestational week. By contrast,
both parieto-occipital and calcarine sulci are, in our
experience, normally recognizable as of the 16th week.
Fig. 1. Three-mm bone defect in the upper part of the occipital bone
without demonstrable meningocele or encephalocele.
In both cases, the internal surface of both parietal and
occipital lobes was abnormally smooth. Considering
the fetal age, the cerebellum was considered normal.
Histologically, the cortical structure was in disarray
in all regions. Different patterns of changes could be
seen according to the cortical topography. The cortical
mantle in the upper and lateral part of the parietal
convexity and in the floor of lateral ventricles was divided into two approximately equal parts by a vascular
band underlined by clusters or laminae of neurons with
only scarce and focal areas of radial alignment. The
outer part was made of neuronal and glial cells arranged in irregular nests or bands dissociated by
bundles of white matter. The disorganized neurons and
glial cells often extended into the subarachnoid space
(Fig. 3). In the external wall of ventricles, only scarce
neurons remained beneath the above described vascular band. Neurons seemed to have migrated to the
outer part of mantle where they appeared interspersed
Fig. 2. Marked dilatation of lateral ventricles with irregular thinning of
the surrounding brain tissue with interhemispheric adhesion without cortical joining and smooth cortical surface.
Walker-Warburg Syndrome
cystic right kidney (Fig. 5) containing 5 cysts of 4 to 8
mm diameters, and several cortical microcysts. The
main cysts responded to largely dilated calices associated with pelviureteric junction fibrous stenosis. Hydronephrosis and tubular or glomerular subcapsular
cysts in an otherwise conserved renal architecture
were found in the surrounding kidney. Only mild cortical changes related to the urinary obstruction could
be observed. The left kidney was normal. No ductal
plate malformation could be found in the liver.
Fig. 3. Total disturbance of the brain structure in the outer part of
cortex: neuronal and glial cells arranged in irregular nests or bands dissociated by bundles of highly vascularized connective tissue (a). Neurons
and glial cells extending into the subarachnoid space (b) H.E.: ×200.
with connective tissue and capillaries and formed disorganized neuronal and glial waves beneath and in the
subarachnoid space. Similar cell disorganization could
be found at the mesencephalic level but the aqueduct of
Sylvius was normal. No growth anomaly of the ocular
globes was found. Lenses were normal but retinal dysplasia was clearly demonstrated, characterized by gliovascular proliferation in the inner retinal layers and
rosettes (Fig. 4).
Histologic structure of the ilio-psoas and ocular
muscles was normal as compared with age-matched
controls. Few myotubes were scattered among myofibers whose cytoplasm was normal. Neither myofiber
size variation nor increase in the amount of endomysial
or perimysial connective tissue could be demonstrated.
In the third sib, abdominal dissection showed a huge
Fig. 4. Retinal dysplasia: gliovascular proliferation in the inner retinal
layers and rosettes. H.E.: ×200.
The diagnostic criteria for WWS are clearly delineated: cobblestone lissencephaly with variable gyral
malformation, diffuse white matter abnormality, retinal abnormality, and congenital muscular dystrophy
by 1 year [Dubowitz and Fardeau, 1995]. The structural cerebral changes observed in both the second and
the third sib were similar to those previously described
in fetal cases of WWS [Miller et al., 1991; Squier, 1993].
The association of cortical dysplasia, retinal dysplasia,
and atretic encephalocele led us to the diagnostic hypothesis of WWS in spite of the lack of muscle dystrophic changes. This diagnosis was further supported by
the family history.
These cases illustrate the diagnostic problems in
Fig. 5. Cystic changes in the right kidney related to pelviuretic junction
Gasser et al.
ultrasonographic and histopathologic assessment of
WWS in the fetal period. Hydrocephalus was present in
all three of our cases, and ventriculomegaly with or
without macrocephaly was present in 40/41 cases of
WWS reviewed by Dobyns et al. [1989]. Thus, the detection of hydrocephalus in a fetus at risk for WWS
should be considered presumptive evidence in support
of the diagnosis. By contrast, while many other malformations in major systems of the body can be detected
prenatally by fetal ultrasonography, lissencephaly cannot be diagnosed with confidence by this method. No
ocular malformation could be detected ultrasonographically in our cases. If ocular anomalies are rather
characteristic for WWS, ultrasound examination seems
to be most often not relevant to such a diagnosis [Miller
et al., 1991; Denis et al., 1993; Rodgers et al., 1994]
during the second trimester. The prenatal diagnosis of
retinal detachment has been reported only after 32
weeks [Farrell et al., 1987; Vohra et al., 1993; Chitayat
et al., 1995]. Thus, the presence of eye malformation
may provide additional supportive evidence for prenatal diagnosis of WWS but its absence does not exclude it.
Therefore, postmortem studies are necessary to obtain histopathologic evidence of diagnosis. The occurrence of such rather uncommon findings as renal
anomalies in the third sib, and the lack of muscle
changes in both the second and the third sib, illustrated difficulties in establishing the diagnosis of WWS
in a fetus not known to be at risk for this disorder.
The association skull defect—right dysplastic kidney
in the third sib led us to consider the possibility of
Meckel syndrome (MS). Some findings argued this hypothesis. The polycystic renal changes in MS are bilateral, in contrast with the unilateral lesions seen in this
fetus. Moreover, the histologic lesions were not consistent with MS: these responded to a huge renal pelvis
distention with hydronephrosis, conserved renal architecture, and presence of tubular and glomerular subcapsular cysts [type IV dysplasia in OsathanondhPotter classification [1964]. Such lesions are not consistent with MS but have been described in fetal
obstructive uropathies [Gasser et al., 1993]. Moreover,
the congenital hepatic fibrosis characteristic of MS
could not be demonstrated. The relation between renoureteral anomalies and WWS is unclear. In those studies where urograms were performed [Whitley et al.,
1993], these were normal. To our knowledge, only one
fetal case of WWS with bilateral hydronephrosis has
been reported in a 38-week fetus by Denis et al. [1993].
The expected muscle changes included endomysial
and perimysial fibrosis, increase in the variability of
fiber sizes, varying degrees of myofiber necrosis, and
inflammatory infiltrate [Lichtig et al., 1993]. By contrast, muscle normality in our cases was critical to the
diagnosis of WWS. The absence of muscular abnormality in WWS has been mentioned, especially before birth
and in the first year of life [Dobins et al., 1989; Dubowitz, 1996]. None of the reported fetal observations of
WWS (age range from 18 to 32 weeks) showed dystrophic changes [Miller et al., 1991; Denis et al., 1993;
Squier, 1993; Voit in Dubovitz, 1996; Bornemann et al.,
1996]. It must be emphasized that the lack of muscle
changes cannot exclude the diagnosis of WWS: the
variability in the age of onset and severity of muscle
dystrophy has already been underlined [Dobyns et al.,
1989; Dubowitz and Fardeau, 1995]. Whereas Miller et
al. [1991] noted histologic muscle changes in a 1-dayold infant with WWS, most histopathologic active degenerative changes in muscles have not been reported
sooner than the third month of life [Miyake et al., 1977;
Lichtig et al., 1993]. This suggests that overt muscular
dystrophy occurs during a late fetal period and even in
the postnatal period as has been described in Fukuyama syndrome [Takada et al., 1987] and in Duchenne
muscular dystrophy. These data seem of interest with
respect to the prenatal histopathologic diagnosis of
WWS, which is probably compatible with the lack of
muscular changes.
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