00:01
What are the common
clinical symptoms,
clinical scenarios,
and presenting features
in NF1 patients?
Well, the first thing to think about
is Cafe-au-lait macules.
00:10
And that's the most
common initial symptom
that is present
in these patients.
00:15
Cafe-au-lait macules,
as you see here
on the image on the far left,
are well circumscribed,
that sharply demarcated
hyperpigmented lesions.
00:24
We heard that
greater than six is sufficient
to establish the diagnosis
and that's based on this really neat
study performed back in the 1990s,
that showed that the likelihood
of making a diagnosis of NF,
which you see on the Y axis.
00:38
It increases with an increased
number of cafe-au-lait macules.
00:41
In fact, in patients who had six
or more cafe-au-lait macules,
almost 80 to 100% of them
were diagnosed with NF1.
00:48
In contrast, patients who had
less than six cafe-au-lait macules,
none of those patients
were diagnosed with NF1.
00:55
So we all can have a birthmark.
And that's no problem.
00:58
We can even have
two, or three, or four.
01:00
But patients who have six or more
cafe-au-lait macules or birthmarks,
that should tip us off to look for
other clinical features of NF1.
01:08
The most common second feature
that we'll see is depicted here.
01:12
This is axillary,
an inguinal freckling.
01:15
Freckling,
where the sun doesn't shine.
01:17
That's not typical.
Freckles can happen anywhere,
and the shunt <inaudible>
can contribute to those,
but not commonly in the
axilla or inguinal area.
01:26
So freckling in those areas should
tip us off that that's not the sun
that caused that freckle,
that may be a genetic condition,
like NF1.
01:33
And it turns out, that's the most
common second contributing factor
that contributes
to the diagnosis of NF1.
01:42
The other thing to think about
is the eyes.
01:43
And here we see depicted
a Lisch nodule,
which is called
an iris hamartoma.
01:48
This is basically
a cafe-au-lait macule
that's on the iris,
that outer part
right around the pupil.
01:54
The thing that we see
with color.
01:57
Here we can see
several browns spots,
hyperpigmented lesions
in the iris,
and these are iris hamartomas,
Lisch nodules.
02:05
Those are very uncommon
in young kids.
02:08
And we can see here at individuals,
the age of between zero and two,
very few patients
have Lisch nodules.
02:15
But by the time
that a patient is 21,
almost 90% of NF patients
will have a Lisch nodules.
02:21
So in adults, this is a really
helpful clinical sign.
02:25
And an eye exam is a
very helpful examination
to establish a diagnosis
of NF1 in adults.
02:32
What other things
do we see in patients?
We'll walk through
neurofibromas.
02:36
That second clinical criterion
was a neurofibroma,
a tumor of the nerve.
02:42
The nerves are in
all parts of the bodies.
02:44
The deep nerves are
named inside the body
and tumors of those deep nerves
we call plexiform neurofibromas.
02:51
The nerves then travel outside
all the way to the surface
of the skin,
and tumors can develop anywhere
along the path of that nerve.
02:58
The nerves that are out
on the very surface of the skin,
tumors that develop in those nerves
we call cutaneous neurofibromas.
03:04
They're soft, they're fleshy,
they're pedunculated.
03:07
You can see them, and feel them,
and squeeze them,
and it will cause no pain.
03:11
And those cutaneous neurofibromas
can be cosmetically unappealing,
but it have no risk of
malignant transformation.
03:17
They won't become a cancer.
03:20
The second type of
neurofibroma that we see
are subcutaneous neurofibromas.
03:24
These develop in the
dermal layer of the skin
just below the epidermis.
03:28
They're still tumors of the nerves,
but they develop slightly lower.
03:33
And they cause, they push out
on the surface of the skin
and you see this bump
that could be painful.
03:39
They're not soft and fleshy,
like the cutaneous neurofibromas,
but you can feel them,
and push on them,
and it may cause pain.
03:46
And those nodules are occurring
deeper underneath the skin.
03:49
They're also can be
cosmetically unappealing,
they can be painful,
or in areas that cause problems
like the belt line
or where you hold a pin,
and could be surgically removed
for those reasons.
03:59
But there is also
no malignant potential
for those
subcutaneous neurofibromas,
like you see here.
04:06
The last type of neurofibroma
is a plexiform neurofibroma.
04:10
These are also
tumors of the nerves
just like each of the ones
that you see.
04:15
But these tumors are occurring deep
in those deep highways of nerves
that are occurring in the arms,
typically legs,
or sometimes in the face.
04:23
They occur in the name nerves.
04:25
And you can see here,
a large plexiform neurofibroma
running the length of the
sciatic nerve
in this patient's leg.
04:32
The tumor begins in the nerve
and starts in the nerve,
but you can see here expands
all the way out
to the surface of the skin.
04:38
And likely involves
the bone, the fascia, the muscle,
and all tissue in between.
04:44
Tumors like this extensive tumors
cannot be surgically removed.
04:48
And for many years,
our field is searched,
for treatments for this,
and we'll talk about some treatments
that are emerging
at the end of this talk.
04:56
Here's another example
of neurofibromas,
or rather severe case
of neurofibromas.
05:01
Cutaneous neurofibromas
out on the skin.
05:03
And you can see these nerves
that go to the surface
of the epidermis
have just grown,
and there's unregulated growth.
05:09
Loss of neurofibromin,
loss of that NF1 gene
has result in unregulated growth,
and there are multiple tumors
occurring on the skin.
05:17
These are not painful, but can be
very cosmetically unappealing
and difficult
in terms of this patient's
dressing and other functions,
and would be removed
for those reasons.
05:28
What other manifestations
do we see?
Well, here, we'll walk through
some of the bony abnormalities
that can occur
as a result of
abnormal bone growth.
05:37
And the two that I want you
to think about
are sphenoid wing dysplasia,
and a tibial bone fracture
with pseudarthrosis.
05:44
Here on the left, you see a great
example of sphenoid wing dysplasia.
05:48
The sphenoid wing is that bone that
sits just beneath the temporal lobe
in the middle cranial fossa,
right behind the maxillary sinus.
05:56
And we can see here
increased bony deposition,
both along the convexity
of the brain on the far left.
06:02
You see that
osteophytic complex,
as well as in the sphenoid wing
to the right.
06:07
And this is a good example
of sphenoid wing dysplasia.
06:10
Similar to some of the
other patients we've seen,
that abnormality
starts in the bone,
but if you look to the tissue that's
in the CT scan out to the surface,
you can actually see that
the entire right face is enlarged
and involved in this tumor,
which can make it very difficultly
to surgically treat.
06:26
The other bony abnormality that
establishes the diagnosis of NF1
is tibial bone fracture
with pseudarthrosis.
06:33
This is a tibial bone that
has been incorrectly formed,
it is weak,
as a result of all those
NF1+/- cells
that are haploinsufficient.
06:43
They have one NF1 copy,
but that mutation is insufficient
for normal cell growth.
06:48
And so the bone is weak
and can break.
06:50
And this patient has suffered
a tibial bone fracture
that has been unable to heal.
06:55
And as a result of that
inability to heal,
we see a false joint.
06:58
It looks like a joint in the
middle of the tibia and fibula,
but it's not.
It's where a normal bone should be.
07:05
And this is a
diagnostic criterion for NF1.
07:09
Lastly, let's think about
some of the things
that can form in the brain.
07:13
And the classic tumor
that develops in the brain
is listed here.
It's an optic pathway glioma.
07:19
These are
pilocytic astrocytoma.
07:21
They're those grade 1
low-grade tumors.
07:24
and they're very common occurring
in about 20% of NF1 patients.
07:30
We'll walk through
what they look like on imaging.
07:32
Here we see the appearance
of a left optic pathway glioma
on this T1-weighted
precontrast imaging.
07:39
They show up as dark on the T1.
07:42
We see some brighter signal
on the T2 image
highlighting this optic nerve.
07:46
This enlarged thickened
sausage like optic nerve
in this patient
on the left optic nerve.
07:54
And they enhance avidly
with contrast.
07:56
And we see here on the
T1-weighted postcontrast image
have an enhancement
on the entire length
of this left optic nerve.
08:03
Many of these patients
will present with vision loss
and that's a common presenting
feature of an optic pathway glioma.
08:09
But it turns out
about 60% of patients
will not suffer any symptoms
from this tumor.
08:14
About a third of those
patients can be watched.
08:16
A third of the patients
may need treatment for this,
but have normal visual function
and no symptoms.
08:22
So important for these patients
to be evaluated
by a multidisciplinary team.
08:28
There are many
manifestations of NF1,
how do we keep them all straight?
Well, not all of those symptoms
we see in every patient.
08:36
And it turns out that the
clinical manifestations of NF1
vary over the course of life.
08:42
In infancy, we think about
Cafe-au-lait macules.
08:45
They are the most
common presenting symptom.
08:47
And so when young children,
pediatricians, and other providers
should think to look for
cafe-au-lait macules.
08:53
And an NF1 patient will have almost
all of their cafe-au-lait macules,
by two years of age.
08:58
And so that's the first thing
we look at.
09:00
During childhood,
we look at other clinical features
that can help us to establish
that second criterion
and make the diagnosis of NF1.
09:07
And typically we're looking for
axillary and inguinal freckling,
vascular abnormalities in
the optic pathway glioma.
09:14
Patients who develop
an optic pathway glioma
typically will develop that
before the age of seven or 11.
09:20
And after the teenage years,
there's no likelihood of that tumor
that optic pathway glioma
contributing to vision loss
or other symptoms.
09:28
In puberty, therefore,
we look at other things.
09:30
We worry about bony abnormality
until the bones have formed.
09:34
And the growth plates
have solidified.
09:37
Neurofibromas often start
to develop during puberty,
and can develop all throughout
the entirety of life.
09:43
New ones can occur,
and the ones that patients have
can increase in size.
09:47
We saw how Lisch nodules
are uncommon in young children,
but increased with age,
and by the time of 19, 20, 21,
the vast majority of NF1 patients
will have evidence of Lisch nodules.
09:58
And then in adulthood,
we about other things.
10:01
We worry about
vascular abnormalities,
and high blood pressure
from pheochromocytomas.
10:05
There's an increased risk
of early onset breast cancer
that all patients
should be screened for.
10:09
And we worry about some changes with
vision and early onset cataracts.
10:13
All throughout life,
we see learning disabilities,
and about 75% of patients.
10:17
That's really important
to screen for monitor
throughout the entirety
of these patients course.