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Holoprosencephaly and polydactyly: A possible expression of the hydrolethalus syndrome

Authors:
H Bachman
H Bachman
H Bachman
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R D Clark
R D Clark
R D Clark
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Walid Salahi at Lundquist Institute
Walid Salahi
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Abstract and Figures

We report two fetuses with hydrocephalus, features of holoprosencephaly, and postaxial polydactyly born to a consanguineous Mexican-American couple. The phenotype is consistent with the hydrolethalus syndrome, although holoprosencephaly has not previously been seen in this condition. We believe other similar cases with a trisomy 13 phenotype but normal chromosomes may also have the hydrolethalus syndrome.
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5
Med
Genei
1990;
27:
50-52
Holoprosencephaly
and
polydactyly:
a
possible
expression
of
the
hydrolethalus
syndrome
H
Bachman,
R
D
Clark,
W
Salahi
Abstract
We
report
two
fetuses
with
hydrocephalus,
features
of
holoprosencephaly,
and
postaxial
polydactyly
born
to
a
consanguineous
Mexican-American
couple.
The
phenotype
is
consistent
with
the
hydrolethalus
syndrome,
although
holoprosen-
cephaly
has
not
previously
been
seen
in
this
condition.
We
believe
other
similar
cases
with
a
trisomy
13
phenotype
but
normal
chromosomes
may
also
have
the
hydrolethalus
syndrome.
In
1981,
Salonen
et
all
first
described
a
lethal
malformation
syndrome
in
28
Finnish
newborns,
which
they
called
hydrolethalus.
Named
for
the
key
features
of
hydramnios,
hydrocephalus,
and
lethality,
hydrolethalus
is
an
autosomal
recessive
condition
also
associated
with
polydactyly,
micrognathia,
microph-
thalmia,
congenital
heart
defect,
and
abnormalities
of
the
respiratory
system.
In
1987,
Anyane-Yeboa
et
a12
delineated
the
condition
further,
noting
midline
brain
abnormalities.
We
describe
two
sibs
from
a
consanguineous
union
who
had
many
of
the
features
of
hydrolethalus
and
holoprosencephaly.
Case
report
At
15
weeks'
gestation,
a
29
year
old
G4,P2,TAB1
Mexican
woman
with
two
normal
daughters
sought
medical
attention
for
a
fever
of
40°C
owing
to
pyelonephritis.
A
routine
fetal
ultrasound
was
done
which
showed
an
omphalocele,
hydrocephalus,
hypotelorism,
and
microphthalmia.
An
amniocentesis
indicated
a
46,XY
normal
male
karyotype
and
normal
amniotic
a
fetoprotein.
The
pregnancy
was
electively
terminated
at
18
weeks'
gestation.
On
examination
of
the
fetus,
cebocephaly,
bilateral
microphthalmia,
omphalocele,
and
postaxial
polydactyly
of
the
left
hand
and
foot
were
noted
(fig
1).
Trachea
and
bronchi,
lobulation
of
the
lungs,
and
the
heart
were
normal.
There
was
no
dorsal
cleft
through
the
occiput,
and
the
shape
of
the
foramen
magnum
was
normal.
The
frontal
bone
was
missing.
The
brain
showed
holoprosencephaly
of
the
lobar
type.
There
was
a
large
common
ventricle
and
the
dorsal
thalamus
and
basal
ganglia
were
dysplastic,
fused
into
a
midline
mass
on
the
posterior
inferior
ventricular
wall.
In
addition,
there
was
agenesis
of
the
olfactory
nerves,
optic
nerves,
oculomotor
nerves,
corpus
callosum,
septum
pellucidum,
hippocampal
formation,
and
the
descending
tracts,
including
the
corticospinal
tract.
The
cerebellum
was
severely
hypoplastic
and
there
was
dysplasia
of
the
midbrain,
pons,
and
inferior
olivary
nuclei.
Microscopic
examination
of
the
cerebral
cortex
showed
the
usual
trilaminar
pattern
of
immaturity,
and
the
cerebellar
cortex
was
normal.
Division
of
Medical
Genetics,
Department
of
Pediatrics,
Harbor-UCLA
Medical
Center,
1124
W
Carson
Street,
Bldg
E-4,
Torrance,
California
90502,
USA.
H
Bachman,
R
D
Clark
Department
of
Pathology,
Harbor-UCLA
Medical
Center,
Torrance,
California
90502,
USA.
W
Salahi
Correspondence
to
H
Bachman.
Received
for
publication
17
April
1989.
Revised
version
accepted
for
publication
7
June
1989.
Figure
I
Postmortem
view
of
case
I
showing
single
nostril,
omphalocele,
postaxial
polydactyly
of
left
hand
and
foot,
and
splayed,
broad
hallux.
so
copyright. on February 3, 2023 by guest. Protected byhttp://jmg.bmj.com/J Med Genet: first published as 10.1136/jmg.27.1.50 on 1 January 1990. Downloaded from
Holoprosencephaly
and
polydactyly:
a
possible
expression
of
the
hydrolethalus
syndrome
Figure
2
Postmortem
view
of
case
2
showing
microphthalmia
and
premaxillary
agenesis
causing
the
midline
facial
defect.
It
was
discovered
that
a
previous
pregnancy
had
been
electively
terminated
by
prostaglandin
induction
at
20
weeks
after
hydrocephalus
was
seen
on
ultra-
sound.
A
necropsy
of
this
male
fetus
showed
pre-
maxillary
agenesis,
microphthalmia,
hydrocephalus,
and
postaxial
polydactyly
of
the
hands
and
left
foot
(fig
2).
The
brain
showed
micropolygyria
and
an
incomplete
Sylvian
fissure
bilaterally
with
total
absence
of
the
aqueduct
of
Sylvius.
In
addition,
cranial
nerves
I
and
II,
the
corpus
callosum,
and
descending
tracts
including
the
corticospinal
tract
were
absent.
The
midbrain,
pons,
and
inferior
olivary
nuclei
were
dysplastic.
Chromosome
studies
were
not
performed.
The
family
history
is
remarkable
because
the
parents
are
third
cousins.
There
are
no
other
affected
relatives,
although
our
patient
reports
that
she
had
a
sister
who
died
at
a
few
days
of
age
with
a
large
head.
No
records
are
available
for
this
child
who
was
born
in
Mexico.
Discussion
We
believe
that
our
patients
have
the
hydrolethalus
syndrome,
as
they
exhibit
almost
all
of
its
features:
hydrocephalus,
midline
structural
defects
of
the
brain,
microphthalmia,
omphalocele,
and
postaxial
polydactyly.
Our
patients
did
not
have
defects
of
the
heart
or
lung.
The
absence
of
polyhydramnios
may
not
be
valid
in
our
cases
because
both
pregnancies
were
terminated
by
20
weeks'
gestation.
The
most
common
abnormality
in
the
feet,
duplication
of
the
hallux,
was
lacking;
hoWever,
our
patients
did
have
large,
deviated
big
toes.
Finally,
the
consanguinity
in
this
family
supports
such
an
autosomal
recessive
trait.
Although
holoprosencephaly
has
not
specifically
been
described
as
a
feature
of
hydrolethalus,
in
their
initial
report
Salonen
et
all
described
the
absence
of
midline
brain
structures in
eight
of
28
cases.
The
most
detailed
description
of
absent
midline
brain
structures
was
provided
in
a
case
report
by
Anyane-Yeboa
et
al.2
In
that
case,
gyral
patterns
were
abnormal
and
olfactory
bulbs,
tracts,
and
the
anterior
commissure
were
absent.
The
thalami
were
fused
and
mammillary
bodies
could
not
be
identified.
Aughton
and
Cassidy3
described
a
mild
case
of
hydrolethalus
with
an
absent
septum
pellucidum
and
a
partial
posterior
defect
in
the
corpus
callosum.
Krassikoff
et
al'
reported
a
patient
with
hydrolethalus
in
whom
massive
hydro-
cephalus
and
holoprosencephaly
were
noted
pre-
natally
by
ultrasound.
At
necropsy,
in
addition
to
bilateral
postaxial
polydactyly
of
the
hands,
the
most
striking
feature
was
a
large
midline
facial
defect
with
absent
nasal
bone
and
cartilages
and
midline
cleft
lip
and
palate.
The
pituitary,
corpus
callosum,
and
septum
pellucidum
were
also
absent.
The
lateral
ventricles
communicated
via
the
subdural
space,
which
resulted
in
the
appearance
of
holoprosen-
cephaly
noted
on
ultrasound.
Thus,
although
holoprosencephaly
in
itself
is
not
stressed,
absence
of
midline
brain
structures
is
well
documented
in
the
hydrolethalus
syndrome.
Similar
patients,
resembling
a
trisomy
13
pheno-
type
with
holoprosencephaly
and
postaxial
poly-
dactyly
may
also
represent
hydrolethalus.
In
1987,
Young
and
Madders5
reported
a
previously
un-
described
syndrome
of
holoprosencephaly,
heart
defects,
and
postaxial
polydactyly
with
normal
chromosomes.
That
stillborn
male
had
premaxillary
agenesis
with
bilateral
microphthalmia,
postaxial
polydactyly
of
the
hands,
alobar
holoprosencephaly
with
absence
of
midline
structures,
pachygyria,
and
a
ventricular
and
atrial
septal
defect.
The
following
year
Moerman
and
Fryns6
reported
a
stillborn
female
with
normal
chromosomes
and
similar
findings:
holo-
prosencephaly
with
alobar
hydrocephalus,
bilateral
postaxial
polydactyly,
neocerebellar
hypoplasia,
and
microphthalmia
with
retinal
dysplasia.
The
authors
considered
hydrolethalus
in
their
differential
diag-
nosis,
but
discounted
it
in
part
because
of
the
holoprosencephaly.
In
addition,
Shiota
and
Tanimura7
described
a
six
week
male
embryo
with
holoprosen-
cephaly
with
absence
of
midline
structures,
cardiac
defects,
and
bilateral
postaxial
polydactyly
in
both
arms
and
legs.
Although
chromosomes
were
not
analysed,
it
is
possible
that
this
embryo
had
the
same
syndrome.
Holoprosencephaly,
in
which
the
embryonic
fore-
brain
fails
to
cleave
sagittally
and
transversely,
can
be
51
copyright. on February 3, 2023 by guest. Protected byhttp://jmg.bmj.com/J Med Genet: first published as 10.1136/jmg.27.1.50 on 1 January 1990. Downloaded from
Bachman,
Clark,
Salahi
caused
by
chromosome
abnormalities,
teratogens,
and
many
single
gene
disorders.
Cohen,8
in
his
largest
and
most
recent
review
of
holoprosencephaly,
lists
seven
autosomal
recessive
syndromes
that
have
holo-
prosencephaly
as
a
feature.
Hydrolethalus
is
not
specifically
mentioned,
although
the
cases
of
Young
and
Madders5
and
Shiota
and
Tanimura7
are
listed
as
'pseudotrisomy
13
syndrome
of
unknown
genesis'.
We
propose
that
holoprosencephaly
is
a
feature
of
the
hydrolethalus
syndrome.
Furthermore,
the
diagnosis
of
'pseudotrisomy
13
syndrome'
in
the
case
of
Young
and
Madders5
and
other
reported
cases
of
holoprosencephaly
and
postaxial
polydactyly
should
be
reconsidered.
These
cases
may
also
represent
hydrolethalus.
Finally,
hydrolethalus
should
be
considered
in
the
differential
diagnosis
of
any
case
of
holoprosencephaly
with
other
anomalies.
1
Salonen
R,
Herva
R,
Norio
R.
The
hydrolethalus
syndrome:
delineation
of
a
"new",
lethal
malformation
syndrome
based
on
28
patients.
Clin
Genet
1981;19:321-30.
2
Anyane-Yeboa
K,
Collins
M,
Kupsky
W,
Maidman
J,
Malin
J,
Yeh
M.
Hydrolethalus
(Salonen-Herva-Norio)
syndrome:
further
clinicopathological
delineation.
Am
Med
Genet
1987;
26:899-907.
3
Aughton
DJ,
Cassidy
SB.
Hydrolethalus
syndrome:
report
of
an
apparent
mild
case,
literature
review,
and
differential
diagnosis.
Am
Med
Genet
1987;27:935-42.
4
Krassikoff
N,
Kolnick
L,
Gilbert
EF.
Ihe
hydrolethalus
syndrome.
Birth
Defects
1987;23(1):411-9.
5
Young
ID,
Madders
DJ.
Unknown
syndrome:
holoprosen-
cephaly,
congenital
heart
defects,
and
polydactyly.
Med
Genet
1987;24:714-5.
6
Moerman
P,
Fryns
JP.
Holoprosencephaly
and
postaxial
poly-
dactyly:
another
observation.
Med
Genet
1988;25:501-2.
7
Shiota
K,
Tanimura
T.
Holoprosencephaly,
ventricular
septal
defect,
and
postaxial
polydactyly
in
a
human
embryo.
Med
Genet
1988;25:502-3.
8
Cohen
M.
Epidemiology,
genetics,
and
syndromology
perspectives
on
holoprosencephaly.
Part
1.
Teratology
1989;40:211-35.
52
copyright. on February 3, 2023 by guest. Protected byhttp://jmg.bmj.com/J Med Genet: first published as 10.1136/jmg.27.1.50 on 1 January 1990. Downloaded from
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  • Aug 1987
  • Am J Med Genet
We present an infant with manifestations of the hydrolethalus syndrome who has survived for over 5 months; previously, the longest survival reported in this condition has been 2 days. The literature is reviewed and the clinical and pathological findings of our patient are compared with those of the 50 previously reported cases. The differential diagnosis of the condition is discussed.
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Perspectives on holoprosencephaly: Part I. Epidemiology, genetics, and syndromology
Article
  • Sep 1989
This paper provides an updated, comprehensive, critical review of the epidemiology, genetics, and syndromic aspects of holoprosencephaly and is divided into four parts. In the first part, epidemiologic aspects are discussed under the following headings: prevalence, temporal trends, socioeconomic status, exposure to environmental teratogens, maternal and paternal ages, pregnancy histories, and birth weights. The second part analyzes the facial phenotypes because the genetic and syndromic aspects of holoprosencephaly cannot be understood without knowledge of facial variability and its meaning. Topics discussed include cyclopia, ethmocephaly, cebocephaly, median cleft lip, and less severe facial dysmorphism. The third section, on genetics, analyzes associated anomalies, chromosomal and non-chromosomal holoprosencephaly, family studies, twin studies, genetics of nonsyndromic holoprosencephaly, and recurrence risks. The final section on syndromology summarizes 48 conditions in which some degree of holoprosencephaly may be a feature.
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Hydrolethalus (Salonen-Herva-Norio) syndrome: Further clinicopathological delineation
Article
  • Apr 1987
Two brothers with severe CNS abnormalities, cleft lip/palate, polydactyly, and lung hypoplasia are reported as examples of the hydrolethalus syndrome, an autosomal recessive disorder. Death from cardiopulmonary arrest occurred in patient 1 at age 4 months and in patient 2 at age 17 days. Detailed radiological and neuropathological description is provided on patient 2. We recommend realtime ultrasonography and, when indicated, fetoscopy for antenatal detection of the craniofacial and limb malformations associated with this syndrome.
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Unknown syndrome: HoloprosencephalY, congenital heart defects, and polydactyly
Article
  • Dec 1987
We present a stillborn male infant with premaxillary agenesis, bilateral microphthalmos, alobar holoprosencephaly, hydrocephalus, ventricular and atrial septal defects, small penis, bilateral cryptorchidism, and bilateral upper limb postaxial polydactyly.
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The hydrolethalus syndrome: Delineation of a 'new', lethal malformation syndrome based on 28 patients
Article
  • Jun 1981
We describe a lethal malformation syndrome in 28 newborn infants from 18 families. The main manifestations were hydrocephalus (often with an unusual structure of the brain and the occipital bone), very small mandible, polydactyly, congenital heart defect, abnormalities of the respiratory organs, and (different from the Meckel syndrome) normal kidneys. Polyhydramnios and stillbirth or neonatal death were the rule. Autosomal recessive inheritance is evident. This syndrome is another in the group of rare recessive disorders which are found in Finland. Because of the 25% recurrence risk and possibilities for prenatal diagnosis, this syndrome should be recognized by paediatricians and, because of the frequent stillbirths, also by obstetricians and pathologists. The name hydrolethalus syndrome (hydramnios, hydrocephalus, lethality) may be of help in this.
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Ihe hydrolethalus syndrome
  • Jan 1987
  • 411-419
  • N Krassikoff
  • L Kolnick
  • E F Gilbert
Krassikoff N, Kolnick L, Gilbert EF. Ihe hydrolethalus syndrome. Birth Defects 1987;23(1):411-9.