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Restrictive dermopathy: A report of three cases

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We report three infants with a rare syndrome of restrictive dermopathy, in which rigidity of the skin at birth is associated with characteristic facial anomalies, generalised arthrogryposis, bony abnormalities, and lung hypoplasia. The skin has a distinctive pathology with compaction of the dermal collagen and fibrosis of the subcutaneous tissue. The inheritance is likely to be autosomal recessive and the condition appears to be fatal in the early neonatal period.
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JMedGenet
1990;
27:
315-319
Restrictive
dermopathy:
a
report
of
three
cases
Q
Mok,
R
Curley,
J
L
Tolmie,
R
A
Marsden,
M
A
Patton,
E
G
Davies
Abstract
We
report
three
infants
with
a
rare
syndrome
of
restrictive
dermopathy,
in
which
rigidity
of
the
skin
at
birth
is
associated
with
characteristic
facial
anomalies,
generalised
arthrogryposis,
bony
abnormalities,
and
lung
hypoplasia.
The
skin
has
a
distinctive
pathology
with
compaction
of
the
dermal
coliagen
and
fibrosis
of
the
subcutaneous
tissue.
The
inheritance
is
likely
to
be
autosomal
recessive
and
the
condition
appears
to
be
fatal
in
the
early
neonatal
period.
Several
cases
of
the
fetal
akinesia/hypokinesia
deformation
syndrome
have
been
described,
where
facial
anomalies,
arthrogryposis,
and
lung
hypoplasia
are
associated.
Examples
include
Pena-Shokier,
Neu-
Laxova,
cerebro-oculo-facio-skeletal,
and
lethal
Departments
of
Child
Health,
Dermatology,
and
Medical
Genetics,
St
George's
Hospital
Medical
School,
London.
Q
Mok,
R
Curley,
R
A
Marsden,
M
A
Patton,
E
G
Davies
Duncan
Guthrie
Institute
of
Medical
Genetics,
Glasgow.
J
L
Tolmie
Correspondence
to
Dr
Mok,
Queen
Mary's
Hospital
for
Children,
Carshalton,
Surrey
SM5
4NR.
multiple
pterygium
syndromes.
Restrictive
dermo-
pathy
is
a
distinctive
and
recendy
described
disorder
in
which
the
primary
defect
appears
to
be
rigidity
of
the
skin,
causing
secondary
generalised
flexion
contractures
and
restriction
of
respiratory
move-
ments,
thus
leading
to
early
death.
Case
reports
CASE
1
Case
1
was
the
first
child
of
healthy,
non-consan-
guineous,
Caucasian
parents.
The
mother, aged
24
years,
did
not
smoke
or
drink
and
was
not
exposed
to
any
known
teratogens.
The
family
history
is
otherwise
unremarkable.
The
pregnancy
proceeded
normally
until
spontaneous
rupture
of
membranes
at
28+
weeks'
gestation,
when
an
ultrasound
scan
showed
a
normal
amount
of
liquor
and
no
fetal
breathing
movements.
Despite
treatment
with
ritodrine
and
dexamethasone
labour
progressed
and
five
days
later
a
male
infant
was
delivered
with
difficulty
by
forceps.
He
had
an
Apgar
score
of
2
at
one
minute
and
was
intubated
at
two
minutes
with
difficulty
because
of
a
small,
tight
mouth
and
restriction
in
neck
extension.
The
placenta
weighed
530
g
and
had
three
vessels.
The
infant
weighed
1080
g
(above
the
10th
centile)
with
an
occipitofrontal
circumference
(OFC)
of
27
cm
(below
the
50th
centile).
He
had
a
dorsal
kyphosis,
rockerbottom
feet,
and
contractures
of
all
the
joints
(fig
1)
including
the
fingers
and
mandible.
The
facial
Figure
I
Case
I
showing
severe
contractures
of
all
the
joints.
Received
for
publication
12
October
1989.
Revised
version
accepted
for
publication
18
December
1989.
315
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Mok,
Curlev,
lolmie,
Marsden,
Patton,
Davies
appearance
was
distinctive
with
an
antimongoloid
slant
and
hypertelorism,
small
pinched
nose,
micro-
stomia
with
a
small,
open,
0
shaped
mouth,
and
micrognathia
(fig
2).
The
anterior
fontanelle
was
large
with
wide
sutures.
At
birth
he
was
noted
to
have
smooth,
shiny
skin
which
felt
rigid
and
tethered.
The
cutaneous
vasculature
was
easily
visible,
suggesting
thinning
of
the
dermis.
Within
hours
of
birth,
fragile
...
blisters
had
developed
over
the
anterior
abdominal
.s#
wall
and
extensor
aspect
of
the
elbows,
and
these
later
ruptured
to
leave
superficial
erosions
(fig
3).
The
2:,
hair
and
nails
were
normal.
Initially
adequate
gas
exchange
was
easily
obtained
on
low
pressure
ventilation
but
his
lungs
became
progressively
more
difficult
to
ventilate.
The
skin
continued
to
break
down
readily
and
became
more
rigid.
Karyotyping
showed
normal
46,XY
chromosomes.
X
rays
showed
deficient
ossification
of
the
distal
clavicles
with
segmentation,
and
the
long
bones,
especially
the
humeri,
showed
'overmodelling'
(fig
4).
A
skin
biopsy
from
the
edge
of
a
blister
showed
parakeratosis
of
the
epidermis
and
a
subepidermal
..f
-
split.
The
dermis
appeared
compacted
with
loss
of
the
t
.
normal
space
between
collagen
bundles,
and
there
were
striking
downward
projections
of
fibrous
tissue
extending
from
the
dermis
into
the
subcutaneous
fat.
Figure
3
Close
up
of
the
skin
showing
the
superficial
erosions.
The
adipose
tissue
itself
was
increased
in
amount
and
contained
proliferating
fibroblasts
(fig
5).
Supportive
treatment
was
withdrawn
in
view
of
the
deteriorating
condition
and
poor
prognosis,
and
the
infant
died
aged
1
week.
CASE
2
Case
2
was
the
second
child
of
consanguineous
Pakistani
parents.
His
mother,
aged
21
years,
took
triiodothyronine
for
hypothyroidism
and
remained
euthyroid
throughout
pregnancy.
The
pregnancy
was
normal
until
32
weeks'
gestation
when
spontaneous
rupture
of
membranes
was
followed
by
a
vaginal
delivery.
The
infant
had
an
Apgar
score
of
2
at
one
minute
with
no
response
to
intubation
and
resus-
citation.
He
died
at
30
minutes.
The
placenta
weighed
450
g
and
was
uniformly
pale,
thick,
and
oedematous.
.....:.-.:.
:
t
The
infant
weighed
1300
g
(below
the
10th
centile)
with
an
OFC
of
27
cm
(below
the
3rd
centile).
He
had
an
antimongoloid
slant,
pinched
nose,
microstomia,
and
micrognathia.
The
skin
was
taut
and
shiny,
and
a
horizontal
split
in
the
skin
over
the
thyroid
cartilage
had
been
noted
even
before
attempts
at
intubation
(fig
Fgure2
The
distinctivefacialappearanceofacaseof
6).
There
were
fixed
flexion
deformities
of
the
hips,
restrictive
dermopathy.
Note
the
antimongoloid
slant
and
knees,
elbows,
and
fingers.
The
ankles
and
the
third,
hypertelorism,
small
pinched
nose,
microstomia
with
a
small,
fourth,
and
fifth
toes
were
dorsiflexed.
He
was
noted
open,
0
shaped
mouth,
and
micrognathia.
to
have
long
nails
and
normal
hair.
316
0
group.bmj.com on July 16, 2011 - Published by jmg.bmj.comDownloaded from
Restrictive
dermopathy:
a
report
of
three
cases
~
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..
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_
Figure
4
The
x
ray
illustrates
the
segmentation
of
the
clavicles
and
overmodelling
of
the
humeri,
also
the
typical
appearance
of
hypoplastic
lungs.
Figure
5
The
skin
biopsy
shows
a
compacted
dennis
with
downward
projections
offibrous
tissue
into
the
thickened
subcutaneous
layer
of
adipose
tissue.
'V
Karyotyping
(Giemsa
banded)
showed
46,XY
chromosomes.
X
rays
showed
decreased
ossification
of
the
distal
ends
of
the
clavicles,
and
'overmodelling'
of
the
long
bones.
A
skin
biopsy
was
not
performed.
CASE
3
Case
3
was
the
sib
of
case
2.
She
was
born
at
32
weeks
after
an
uneventful
pregnancy.
Apgar
scores
were
5
at
one
minute
and
7
at
five
minutes.
She
weighed
1500
g
(10th
centile)
with
an
OFC
of
29
cm
(10th
centile).
She
had
exactly
similar
dysmorphic
features
to
the
previous
infant
(fig
7).
The
skin
was
of
similar
appearance
and
texture,
the
nails
were
long,
and
there
were
flexion
contractures
of
the
joints.
She
had
a
normal
46,XX
karyotype.
X
ray
findings
were
similar
to
the
previous
infant.
A
skin
biopsy
showed
acanthosis
and
hyperkeratosis
of
the
epidermis
with
reduction
in
papillary
dermis,
widespread
telangiectasia,
and
poorly
formed
hair
and
sweat
gland
elements.
The
infant
required
tube
feeds
and
over
the
317
I
.,
-.
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11
--
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14
il
9
I
.
group.bmj.com on July 16, 2011 - Published by jmg.bmj.comDownloaded from
Mok,
Curlev,
7olmie,
Marsden,
Patton,
Davies
Figure
6
A
close
up
of
case
2
showing
the
typicalfacial
features
and
the
split
in
the
skin
over
the
thyroid
cartilage
that
was
present
from
birth.
Figure
7
The
postmortem
photograph
of
case
3
showing
all
the
features
of
the
condition
previously
described.
following
six
weeks
the
skin
became
progressively
less
elastic.
Three
primary
teeth
erupted
prematurely.
Cyanotic
attacks
became
more
frequent
and
the
infant
died
aged
7
weeks.
The
parents
had
a
previous
healthy
male
child
and
a
subsequent
healthy
female
child.
They
also
had
two
subsequent
intrauterine
deaths
at
16
and
26
weeks,
respectively.
Necropsy
was
refused
in
all
three
cases.
Discussion
The
term
'restrictive
dermopathy'
was
first
used
by
Witt
et
all
to
describe
two
sibs
from
consecutive
pregnancies,
both
born
prematurely
at
32
weeks.
They
shared
the
clinical,
radiological,
and
histological
features
of
our
three
infants
with
the
characteristic
facial
anomalies
(microstomia,
micrognathia,
hyper-
telorism,
pinched
nose,
low
set
ears,
wide
sutures
and
fontanelles),
arthrogryposis,
pulmonary
hypoplasia,
and
intrauterine
growth
retardation.
Polyhydramnios
was
noted
in
both
pregnancies
and
the
infants
had
short
umbilical
cords.
X
ray
examination
showed
overtubulation
of
the
long
bones
with
segmentation
defects
of
the
clavicles.
In
a
more
extensive
study
of
the
two
sibs
and
a
further
unrelated
infant,
Holbrook
et
a12
defined
histological,
ultrastructural,
and
biochemical
abnormalities
of
the
skin.
They,
like
our
infants,
had
shiny,
rigid
skin
with
distinctive
histology
showing
parakeratotic
hyperkeratosis,
epidermal
acanthosis,
a
dermis
composed
of
dense
parallel
connective
tissue,
and
a
thickened
and
fibrotic
layer
of
subcutaneous
fat.
Hair
follicle
development
appeared
to
have
been
arrested
at
a
stage
corresponding
to
the
follicle
development
in
the
first
or
early
second
trimester
fetus.
Epidermal
extracts,
when
examined
by
gel
electrophoresis
and
stained
with
antikeratin
mono-
clonal
antibodies,
showed
a
pattern
suggestive
of
a
hyperproliferative
state
with
an
increased
expression
of
48
and
56
kD
keratins.
Immunohistochemistry
of
the
epidermis
showed
a
distinctive
staining
pattern
with
the
monoclonal
antibody
AE1,
which
normally
stains
basal
cells,
but
in
the
two
affected
infants
stained
only
suprabasal
cells.
A
number
of
other
infants
with
very
similar
features
have
been
reported
previously.
All
showed
the
typical
facial
anomalies,
joint
contractures,
and
skin
fragility.
Although
Toriello
et
a13
described
two
sibs
as
having
aplasia
cutis
congenita,
their
description
and
photographs
closely
resemble
our
cases.
Necropsy
showed
evidence
of
prematurity
with
patent
arterial
ducts,
immature
brain
gyral
pattern,
and
fetal
lobu-
lations
of
the
kidneys.
Toriello4
subsequently
reported
a
third
sib
born
to
the
same
family
with
all
the
typical
anomalies.
Studies
of
the
skin
by
Holbrook
et
a12
clearly
showed
that
the
infant
has
the
same
condition
as
the
two
sibs
described
by
Witt
et
all
and
318
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Restrictive
dermopathy:
a
report
of
three
cases
termed
restrictive
dermopathy.
The
four
infants
reported
by
Lowry
et
a15
showed
no
internal
abnor-
malities
apart
from
pulmonary
hypoplasia.
One
of
their
cases
also
showed
premature
eruption
of
teeth
and
had
two
central
incisors.
Toriello4
noted
remark-
able
consistency
in
the
facial
phenotypes
in
the
cases
described,
while
the
skin
anomaly
exhibits
more
variable
expression.
The
striking
similarity
of
the
cases
caused
Gillerot
and
Koulischer6
to
review
their
patient's
diagnosis
and
recall
the
family
five
years
later
to
correct
recurrence
risk
figures
and
propose
prenatal
diagnosis.
Schnur
et
a17
identified
large
amounts
of
proline
and
hydroxyproline
containing
small
peptides
in
the
skin
of
an
affected
infant,
and
suggested
a
primary
defect
of
collagen
or
its
metabolism.
Lowry
et
a15
and
Witt
et
all
postulated
that
all
the
abnormalities
were
related
to
a
basic
disorder
of
skin
differentiation.
Rigidity
of
the
skin
caused
severe
restriction
of
movement
in
utero,
and
consequent
contractures.
The
facial
changes
may
be
the
result
of
the
intrinsically
abnormal
mechanical
effects
of
the
skin,
the
pulmonary
hypoplasia
the
result
of
limitation
of
chest
excursion
and
breathing
movements,
and
the
polyhydramnios
the
result
of
abnormal
swallowing.
Toriello4
suggested
that
it
is
a
more
complex
dysplasia
affecting
several
tissues
and,
owing
to
its
effect
on
fetal
movement,
numerous
deformations
are
caused.
Restrictive
dermopathy
is
a
universally
fatal
condition
in
the
neonatal
period.
Efforts
should
therefore
be
directed
towards
confirming
the
diagnosis
rapidly
after
birth
and
minimising
trauma
to
the
infant
and
family.
All
the
reported
cases
suggest
autosomal
recessive
inheritance,
which
is
supported
by
a
history
of
parental
consanguinity
in
many
of
the
families.
In
view
of
the
high
risk
of
recurrence
in
subsequent
pregnancies,
there
is
a
clear
need
for
prenatal
diagnosis
in
potentially
affected
infants.
Regular
detailed
ultra-
sound
scanning
after
16
weeks
could
identify
decreased
fetal
movement
and
joint
contractures,
but
may
be
too
non-specific
in
determining
affected
cases
for
thera-
peutic
abortions.
All
the
epithelial
structural
proteins
are
expressed
by
14
to
16
weeks'
gestation.
Examination
of
fetal
skin
obtained
after
this
time
for
morphological
abnormal-
ities
and
for
the
increased
expression
of
the
48
and
56
kD
keratins
might
be
used
for
prenatal
diagnosis.
The
prospects
for
prenatal
diagnosis
will
improve
if
the
specific
gene
defect
in
this
condition
can
be
determined.
We
thank
Dr
T
L
Turner
for
permission
to
report
cases
2
and
3.
1
Witt
DR,
Hayden
MR,
Holbrook
KA,
Dale
BA,
Baldwin
VJ,
Taylor
GP.
Restrictive
dermopathy:
a
newly
recognized
auto-
somal
recessive
skin
dysplasia.
Am
J
Med
Genet
1986;24:
631-48.
2
Holbrook
KA,
Dale
BA,
Witt
DR,
Hayden
MR,
Toriello
HV.
Arrested
epidermal
morphogenesis
in
three
newborn
infants
with
a
fatal
genetic
disorder
(restrictive
dermopathy).
J
Invest
Dermatol
1987;88:330-9.
3
Toriello
HV,
Higgins
JV,
Waterman
DF.
Autosomal
recessive
aplasia
cutis
congenita-report
of
2
affected
sibs.
Am J
Med
Genet
1983;15:153-6.
4
Toriello
HV.
Invited
editorial
comment:
restrictive
dermopathy
and
report
of
another
case.
Am
J
Med
Genet
1986;24:625-9.
5
Lowry
RB,
Machin
GA,
Morgan
K,
Mayock
D,
Marx
L.
Congenital
contractures,
edema,
hyperkeratosis,
and
intra-
uterine
growth
retardation.
Am
J
Med
Genet
1985;22:531-43.
6
Gillerot
Y,
Koulischer
L.
Letter
to
the
editor.
Restrictive
dermopathy.
Am
J
Med
Genet
1987;27:239-40.
7
Schnur
RE,
Ashmead
J,
Kelley
RI.
A
lethal
ichthyosis
variant
with
arthrogryposis.
Am
J
Hum
Genet
1985;37:76A.
319
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doi: 10.1136/jmg.27.5.315
1990 27: 315-319J Med Genet
Q Mok, R Curley, J L Tolmie, et al.
report of three cases.
Restrictive dermopathy: a
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... [1] Heterozygous mutations documented in ZMPSTE24 gene, its recurrence in families and its association with consanguinity support a simple autosomal recessive mode of inheritance for restrictive dermopathy. [3,4] ZMPSTE24 codes for a zinc metalloproteinase that plays a role in lamin A maturation. In restrictive dermopathy, accumulation of farnesyl-prelamin A occurs at the nuclear membrane. ...
... [7] Genetic analysis to detect ZMPSTE24 mutation and radiological investigations for skeletal changes such as enlarged fontanelles, clavicular dysplasia, and reduced bone density may help in doubtful cases. [1][2][3][4] The differential diagnoses considered in our cases were Pena-Shokeir phenotype, cerebro-oculo-facio-skeletal syndrome, lethal multiple pterygium syndrome, and Neu Laxova syndrome. Predominant features of Pena Shokier phenotype are multiple ankylosis, pulmonary hypoplasia and facial dysmorphism. ...
Article
Full-text available
Restrictive dermopathy is a rare entity that is fatal in the neonatal period itself. The rigidity of the skin leads to erosions, contractures, and restriction of respiratory movements. Diagnosis is often made clinically with classical features such as low-set ears, micrognathia, small, and persistently open fixed “o”-shaped mouth, translucent, shiny, rigid skin with prominent superficial blood vessels, and pseudocontractures of limb joints. We report two cases of restrictive dermopathy observed in our center within 2 years period and suggest that this condition may not be as rare as believed.
... Prenatal signs can include intrauterine growth retardation, reduced fetal movements, polyhydramnios, and premature rupture of the membranes. Most infants die within the first week of life.113 It is mostly caused by mutations in the LMNA gene 114 ; however, insertions resulting in a premature stop codon in the ZMPSTE24 gene have also been found.115 ...
Article
Telomeropathies involve a wide variety of infrequent genetic diseases caused by mutations in the telomerase maintenance mechanism or the DNA damage response system (DDR). They are considered a family of rare diseases that often share causes, molecular mechanisms and symptoms. Generally, these diseases are not diagnosed until the symptoms are advanced, diminishing the survival time of patients. Although several related syndromes may still be unrecognized this work describes those that are known, highlighting that since they are rare diseases, physicians should be trained in their early diagnosis. The aetiology and diagnosis are discussed for each telomeropathy and the treatments when available, along with a new classification of this group of diseases. Ethical and legal issues related to this group of diseases are also considered. This article is protected by copyright. All rights reserved.
... Among the secondary laminopathy, Zmpste24 deletion is also related to segmental progeroid syndrome, Restrictive Dermopathy (RD; 46). Usually, RD patients die within a few weeks of birth due to respiratory failure (47). However, the Zmpste24-/-mouse can live longer than 6 months, although it has a small body size and aging-related phenotypes. ...
Article
Full-text available
Lamin A and its alternative splicing product Lamin C are the key intermediate filaments (IFs) of the inner nuclear membrane intermediate filament. Lamin A/C forms the inner nuclear mesh with Lamin B and works as a frame with a nuclear shape. In addition to supporting the function of nucleus, nuclear lamins perform important roles such as holding the nuclear pore complex and chromatin. However, mutations on the Lamin A or Lamin B related proteins induce various types of human genetic disorders and diseases including premature aging syndromes, muscular dystrophy, lipodystrophy and neuropathy. In this review, we briefly overview the relevance of genetic mutations of Lamin A, human disorders and laminopathies. We also discuss a mouse model for genetic diseases. Finally, we describe the current treatment for laminopathies.
... Thin, translucent, tight skin, as well as joint contractures, respiratory insufficiency, a small pinched nose, micrognathia and mouth in a characteristic fixed 'o' shape are the signs of the disease at birth. Usually respiratory failure due to the tight skin leads to a neonatal death within a few weeks of birth [81,82]. ...
Chapter
Various rare inborn errors of metabolism may present at birth or in early childhood with ‘stiff skin’ and joint contractures. This may be caused by abnormal deposition of hyaline‐like substances in the skin or abnormalities in development of connective tissues such as elastin and collagen. This predominantly dermal process may extend into the subcutis and fascia with fibrosis and scarring. There are four distinctive subtypes: (i) hyaline fibromatosis syndrome (CMG2 gene); (ii) lipoid proteinosis (ECM1 gene); (iii) stiff skin syndrome (fibrillin‐1 gene) and (iv) restrictive dermopathy (primary laminopathy − LMNA gene or secondary laminopathy – ZMPSTE24 gene). There is no specific treatment for these conditions as yet. The infantile form of hyaline fibromatosis syndrome and restrictive dermopathy are usually lethal in infancy. Genetic counselling and genetic testing should be offered to families. Preimplantation diagnosis could be considered for the lethal variants
Article
Arthrogryposis is the term used to describe conditions with nonprogressive multiple congenital contractures. The term is descriptive rather than diagnostic and refers to over 350 specific disorders; in more than one-third of these the responsible gene has been identified. Arthrogryposis occurs in about 1/4000 newborns. This chapter suggests a clinical approach to diagnosis including important elements of pregnancy, delivery, and family history, physical examination, and natural history. Multiple tables help the reader with the differential diagnosis. Prenatal diagnosis, therapy, and laboratory tests are also discussed.
Article
The nuclear lamina, a protein network located under the nuclear membrane, has during the past decade found increasing interest due to its significant involvement in a range of genetic diseases, including the segmental premature aging syndromes Hutchinson-Gilford progeria syndrome, restrictive dermopathy, and atypical Werner syndrome. In this review we examine these diseases, some caused by mutations in the LMNA gene, and their skin disease features. Advances within this area might also provide novel insights into the biology of skin aging, as recent data suggest that low levels of progerin are expressed in unaffected individuals and these levels increase with aging.Journal of Investigative Dermatology advance online publication, 20 August 2015; doi:10.1038/jid.2015.295.
Chapter
Restrictive dermopathy is a lethal genetic skin condition due to a deficiency of lamin A. It is inherited in an autosomal recessive fashion. The skin fails to develop after the second trimester and when the baby is born, the tight skin causes death by respiratory failure typically within a few days. Currently, no treatment is available but genetic testing and prenatal testing are possible.
Article
Full-text available
Restrictive dermopathy is a rare autosomal recessive disorder in which rigidity or tautness of the skin from the second trimester causes a fetal akinesia deformation sequence (FADS) and early death. Characteristic features include taut skin with prominent subcutaneous vessels, widely open fontanelles and cranial sutures, distinctive facies, flexion contractures, pulmonary hypoplasia, sparse eyelashes and and eyebrows, thin dysplastic clavicles. The histologic abnormalities of the skin are located in a thin dermis, consisting of compactly arranged collagen fibers, scanty elastic fiber. The dermoepidermal junction is flat, and epidermal appendages are absent, miniaturized or immature. The presence of adipose tissue may be increased. We report on the first Korean case of restrictive dermopathy with typical clinical features and histological findings.
Article
A brother and sister from consecutive pregnancies had rigid and tightly adherent skin in association with generalized contractures, unusual facies, pulmonary hypoplasia, an abnormal placenta, and a short umbilical cord. Both died shortly after birth. Pathologic examination of the skin by light and electron microscopy showed structural abnormalities of the epidermis, dermis, and subcutaneous fat. An abnormal pattern of keratin proteins was determined biochemically using extracted epidermal proteins. Autopsy showed a normal spinal cord and muscle histology. It is postulated that the defective skin severely restricted movement and secondarily led to the other abnormalities. Familial occurrence is most consistent with autosomal recessive transmission. These patients and the primary skin defect are discussed within the framework of the Fetal Akinesia or Hypokinesia Deformation Sequence.
Article
Two sibs and one unrelated infant were born prematurely with taut, shiny, restrictive skin that was abnormal in structure, organization, biochemistry, and state of differentiation. Prominent abnormalities in all regions of the skin were recognized by light and electron microscopy, immunohistochemistry, and biochemistry. The epidermis was hyperplastic, hyperkeratotic, and parakeratotic. Keratohyaline granules were abnormal in structure, but the keratohyalin-derived protein filaggrin was apparently normal in quantity and biochemistry. The epidermal cells contained less than the expected quantity of high-molecular-weight, differentiation-specific keratins and the tissue stained with antikeratin antibodies in an aberrant pattern. Additional 48 and 56 kD keratin polypeptides, indicative of a hyperproliferative state, were expressed. The dermal-epidermal junction was remarkably flat and the dermis was thinner than normal. The connective tissue appeared stretched and was oriented like tendon rather than dermis. Collagen fiber bundles and fibrils were smaller in diameter than normal. The nails were normal but other epidermal appendages such as the pilosebaceous structures and the eccrine sweat glands were underdeveloped, suggesting that morphogenesis of these structures was arrested at an early stage in utero. The subcutaneous fat was at least twice the thickness of the dermis. The skin abnormalities appeared to be the cause of the flexion contractions, characteristic facies, and inability to survive because of restricted respiratory movements. The structural and biochemical abnormalities in the skin of affected infants may serve as markers for prenatal and postnatal diagnosis of the disorder, and may provide insight into the basic mechanism of the disease.
Article
In 1983, we reported on two sibs whose phenotype was similar to that of the 'aplasia cutis congenita'. A third affected sib has since been born to this family, and this chid was diagnosed by histopathologic skin studies as having the condition called 'restrictive dermopathy' by Witt et al (1986). This case illustrates the phenotypic variability of the skin defect and indicates that the infants in the reports of Toriello et al (1983) and Witt et al (1986) have the same condition. Lowry et al (1985) have also reported a 'syndrome of congenital contractures, edema, hyperkeratosis, and intrauterine growth retardation' that may be the same condition. Comparison of these cases with each other as well as with the 'aplasia cutis congenita' syndrome and epidermolysis bullosa with pyloric atresia syndrome suggests that there is a continuum of lethal skin disorders.
Article
We present clinical findings in infants from three kindreds (two Hutterite and one Mennonite) with an apparently unique, fatal disorder. The major manifestations consist of severe intrauterine growth retardation, congenital contractures, and tense skin which is easily eroded. The skin is tightly drawn over the face, giving an abnormal appearance consisting of a narrow, pinched nose, small mouth, limited jaw mobility, and ectropion (in one). One infant had first-degree hypospadias. Apart from this, there were no organ malformations and the infants did not have hydrops. Histologically, the skin showed hyperkeratosis. It is postulated that this is a tissue dysplasia and that all of the clinical effects are secondary. The disorder appears to be an autosomal recessive trait. The two Hutterite families are from different endogamous subdivisions. They are related as fourth cousins once-removed and fifth cousins in multiple ways through the six nearest common ancestors of all four parents. There are 25 founders (11 couples and three individuals) who are common ancestors. We computed the probability of joint descent of the four alleles in each pair of parents and in a sample of Alberta Hutterite couples, assuming that each of the common founders in turn was the original carrier. For an allele from one particular founder couple, there is a relatively greater probability of identity by descent for each pair of parents than on the average for other couples of the same endogamous subdivision.
Article
Restrictive dermopathy is a rare, fatal, autosomal recessive, congenital skin disease. Rigidity of translucent thin skin, which is thus highly vulnerable and tears, spontaneously causes intra-uterine fetal akinesia or hypokinesia deformation sequence (FADS), characteristic dysmorphic facies with fixed open mouth in O position, and generalized joint contractures (arthrogryposis). Polyhydramnios and pulmonary hypoplasia are distinctive manifestations, leading to respiratory insufficiency and premature delivery at about 31 weeks of gestation. We report on a case of a prematurely born infant who presented with the typical morphological features and describe the light- and electron-microscopical findings as described in the literature.
A lethal ichthyosis variant with arthrogryposis
  • Re Schnur
  • J Ashmead
  • Ri Kelley
Schnur RE, Ashmead J, Kelley RI. A lethal ichthyosis variant with arthrogryposis. Am J Hum Genet 1985;37:76A.