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Targeting epidermal lipids for treatment of Mendelian disorders of cornification.
[child syndrome]
Inherited
ichthyoses
or
Mendelian
disorders
of
cornification
(
MeDOC
)
are
clinically
heterogeneous
disorders
with
high
unmet
therapeutic
needs
,
which
are
characterized
by
skin
hyperkeratosis
and
scaling
.
Some
MeDOC
types
are
associated
with
defects
of
the
epidermal
lipid
metabolism
,
resulting
in
perturbed
barrier
permeability
and
subsequent
epidermal
hyperplasia
,
hyperkeratosis
and
inflammation
.
An
example
is
the
CHILD
(
congenital
hemidysplasia
with
ichthyosiform
nevus
and
limb
defects
)
syndrome
,
an
X-
linked
dominant
multisystem
MeDOC
caused
by
mutations
in
the
NSDHL
(
NAD
(
P
)
H
steroid
dehydrogenase-like
protein
)
gene
,
which
is
involved
in
the
distal
cholesterol
biosynthetic
pathway
.
The
skin
manifestations
of
the
CHILD
syndrome
have
been
attributed
to
two
major
mechanisms
:
deficiency
of
cholesterol
,
probably
influencing
the
proper
corneocyte
membrane
formation
,
and
toxic
accumulation
of
aberrant
steroid
precursors
.
Here
we
addressed
the
efficacy
of
an
ointment
containing
cholesterol
and
simvastatin
,
an
agent
inhibiting
endogenous
cholesterol
synthesis
in
a
compassionate-use
treatment
of
three
patients
with
CHILD
syndrome
.
To
test
the
specificity
of
this
therapeutic
approach
,
we
applied
the
same
topical
treatment
to
two
patients
with
other
types
of
MeDOC
with
disturbed
skin
lipid
metabolism
.
The
therapy
with
simvastatin
and
cholesterol
was
highly
effective
and
well-tolerated
by
the
CHILD
syndrome
patients
;
only
lesions
in
the
body
folds
represented
a
therapeutic
challenge
.
No
improvement
was
noted
in
the
patients
with
other
types
of
MeDOC
.
This
therapy
is
inexpensive
and
accessible
to
every
patient
with
CHILD
syndrome
,
because
both
simvastatin
and
cholesterol
are
available
worldwide
.
Our
data
provide
initial
evidence
of
the
specificity
of
the
therapeutic
effect
of
the
simvastatin-cholesterol
ointment
in
CHILD
syndrome
in
comparison
to
other
types
of
MeDOC
.
Diseases
Validation
Diseases presenting
"clinically heterogeneous disorders"
symptom
child syndrome
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