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Evidence that FGFR1 loss-of-function mutations may cause variable skeletal malformations in patients with Kallmann syndrome.
[kallmann syndrome]
Loss
-of-function
mutations
in
FGFR
1
have
been
identified
in
approximately
10
%
of
the
Kallmann
syndrome
(
KS
)
patients
.
Previous
reports
have
focused
mainly
on
olfactory
,
reproductive
,
and
some
other
features
such
as
cleft
lip
/
palate
and
dental
agenesis
.
Given
the
ubiquitous
expression
of
FGFR
1
during
development
,
other
abnormal
phenotypes
might
,
however
,
have
been
overlooked
in
these
patients
.
Here
,
we
demonstrate
skeletal
phenotypic
characterization
of
patients
presented
with
KS
and
FGFR
1
mutations
.
U
sing
the
Sanger
DNA
sequencing
technique
a
cohort
of
29
KS
patients
was
screened
.
Here
,
we
report
on
5
KS
patients
who
carry
FGFR
1
mutations
(
Gly
270
A
sp
,
Gly
97
S
er
,
Met
161
T
hr
,
Ser
685
Phe
and
Ala
167
S
er
/
Ala
167
S
er
)
.
Three
patients
presented
with
skeletal
abnormalities
,
i
.
e
.
spine
(
hemivertebra
and
butterfly
vertebra
)
and
limb
(
oligodactyly
of
the
feet
,
fusion
of
the
4
th
and
5
th
metacarpal
bones
)
malformations
in
two
patients
and
one
patient
,
respectively
.
The
hand
phenotype
found
in
the
patient
can
not
be
thought
of
as
a
counter-
type
of
the
hand
phenotype
resulting
from
FGFR
1
gain-of-function
mutations
.
The
skeletal
anomalies
identified
in
the
3
KS
patients
are
close
to
those
observed
in
Fgfr
1
conditional
knockout
mice
.
This
study
demonstrates
that
FGFR
1
loss
-of-function
mutations
can
be
associated
with
skeletal
abnormalities
also
in
humans
.
Further
investigations
in
KS
patients
who
carry
FGFR
1
mutations
are
needed
to
evaluate
the
prevalence
of
skeletal
defects
in
this
genetic
form
of
KS
.
Conversely
,
the
presence
of
bone
malformations
in
a
KS
patient
should
direct
the
geneticist
towards
a
search
for
mutations
in
FGFR
1
.
Diseases
Validation
Diseases presenting
"loss-of-function mutations"
symptom
achondroplasia
alpha-thalassemia
aromatase deficiency
child syndrome
cowden syndrome
dystrophic epidermolysis bullosa
epidermolysis bullosa simplex
erythropoietic protoporphyria
esophageal adenocarcinoma
familial hypocalciuric hypercalcemia
harlequin ichthyosis
hirschsprung disease
kallmann syndrome
kindler syndrome
lamellar ichthyosis
neonatal adrenoleukodystrophy
pendred syndrome
werner syndrome
x-linked adrenoleukodystrophy
This symptom has already been validated