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in this lecture we will discuss trisomy
21 or Down syndrome trisomy 21 is when a
patient has three copies of their 21st
chromosome in every cell in their body
these patients have characteristic
facial features like you can see here
they have hypotonia they have
intellectual disability and they may
have congenital malformations and we'll
go through these more carefully in this
lecture so how does this happen
the most common times about 94% of the
time this is from nondisjunction
basically one parent creates two normal
gametes and the other parent creates one
gamete with two copies and the other one
simply isn't viable then through freak
occurence the gamete with two copies
fertilizes a normal egg or the egg has
two copies and is fertilized by a normal
sperm and this results in a patient with
three copies of the 21st chromosome so
this is non disjunction this is about
94% of the time about 6% at a time this
will happen through Robert Sounion
translocation Robert Sony and
translocation is a little bit
complicated so I want to walk you
through it this one time so we all are
on the same page will repeat Robert
Sounion translocations when we talk
about other try Zoe's but here we have a
patient whose normal and a spouse who
has a Robert Sounion translocation this
spouse is completely normal from the
standpoint of how they appear to you or
how they interact with you
this patient has two blue chromosome 14s
I just chose 14 as an example then for
chromosome 21 a piece of it has been
translocated onto the end of one of
those 14 chromosomes so they have the
appropriate amount of chromosomal
material in each cell it's just miss
located with half of one chromosome
being adhered to another that's the
Robert Sounion translocation but now
let's watch what happens when a patient
who has translocation
then goes and has a child with a normal
individual and what happens to the
various opportunities for their
offsprings so let's consider a case
where a parent who has a normal genome
is going to have a baby with a parent
who has a Robert Sounion translocation
the normal parent will make two gametes
these will both be normal one copy of
twenty one which are the red ones and
one copy of fourteen which are the blue
ones
however the parent who is a
translocation carrier will make six
possible gametes and you can see them
all drawn here with the lowest one being
a normal gamete but the others all being
variations now when we these two parents
make an offspring it's possible that
they may make a normal offspring as you
can see in this picture with the lowest
gamete in the translocated carrier
matching up with one of the normal
gametes from the normal patient however
they may also make trisomy fourteen
that's not viable that child will not
come to be or they could create yet
another translocation carrier like the
translocation karien in the first
example this child will grow to be a
carrier of Down syndrome but will not
have any minification x' of Down
syndrome or they could make a Manos Oh
me 21 which is not viable this child
will not come into being or
alternatively they could create a
translocation such that this patient has
Down syndrome they have essentially
three copies of the 21st chromosome one
of them is adhered to their fourteenth
chromosome or alternatively they could
create create Manos only fourteen
that's not viable either so essentially
the odds are for this couple that they
can either have a normal child a child
who is put at risk for creating children
in the next generation in a similar way
or a child with Down syndrome so let's
look now at risks for Down syndrome the
biggest risk that we have to consider is
the maternal age
with women who get older as they get
older it's more and more likely for them
to create eggs that have a extra copy of
a 21st chromosome and you can see the
risk here so generally we consider 35 a
point at which the risk starts to really
come up and after 40 it comes up
dramatically and those are the risks you
can see so let's say we have a baby and
we're wondering whether they might have
Down syndrome this is a diagnosis that's
frequently made on physical exam and
there are some classic physical exam
findings that we can see one is they can
have epicanthal folds or ups landing
fissures of their eyes they may have
mid-face hypoplasia you can see that a
little bit in this child they may have
brachycephalic they may have a little
bit of excessive skin behind the neck
sometimes we can see that in utero on
ultrasound you may see something called
a palmar crease this is where that
crease goes straight across the hand
instead of branching like it normally
does you may see a slight gap between
the first and second toes much like a
flip-flop sandal it's where that
flip-flop post would go and you may see
that gap there and you can see small
white spots in the iris which are called
brush filled spots that can be
associated with Down syndrome patients
with Down syndrome have other issues
that can be more consequential one
example is congenital heart disease and
this can show up in as many as 50
percent of patients and the most common
is what we call an endocardial cushion
defect which is also called the common
AV canal this is when they have both a
VSD and an ASD essentially creating one
large chamber in the heart patients with
Down syndrome are at increased risk for
duodenal atresia about 12 percent of the
time as you can see here they'll have
that classic finding of the double
bubble sign on abdominal x-ray very
early in life they'll present quite
quickly with inability to eat and
inability to defecate and you can see
that double bubble area where one bubble
is the stomach and the other bubble is
the accrual of air before that area of
droite
atresia patients may develop congenital
hypothyroidism this hopefully will be
picked up on their newborn screen if not
we want to address it as quickly as
possible these infants happen have it
about 1% of the time among patients with
Down syndrome and hearing loss and
especially frequent otitis media is
common in patients with Down syndrome as
well they may develop eye disease such
as cataracts or refractive errors they
may develop poor growth in fact patients
with Down syndrome should be plotted
along their own special growth curve
which is available online they may have
increased risk for celiac disease they
may have Atlanta axial instability so
Lela and Lana lacks axial instability is
an instability of c1 on c2 of there
vertebrae we used to recommend x-ray
screening though now we've decided that
is no longer particularly beneficial
although it may be required for
participation in the Special Olympics
which is important for these kids
additionally they may have an increased
risk of leukemia and that is very
important so how do we screen for
patients with Down syndrome it is common
especially in mothers of advanced age to
do standardized routine screening for
Down syndrome generally we will try to
screen in the first trimester or in the
second trimester we can do the triple or
quadruple screen that's very important
also we can do a level 2 fetal
ultrasound screening identifies infants
who are at risk for potential Down
syndrome it is not diagnostic and there
is a absolutely a false positive rate if
they don't want to ever do invasive
testing there is probably no role for
screening but if they do want to do
invasive testing then the screen is a
reasonable thing to do because the next
step would be to invasively tests and
see if that infant truly has Down
syndrome the way we would do definitive
testing in utero is generally through
chorionic villus sampling this happens
around 10 to 12 weeks of gestation or we
can do amniocentesis or
sixteen to twenty weeks of gestation the
ideas were going in getting actual cells
from the actual baby and then doing a
karyotype to figuring out what their
genetic potential is so we're gonna send
that for karyotype
here's a karyotype this is how we would
confirm a diagnosis or do an in utero
diagnosis it confirms essentially
whether that patient has either a
translocation or as a de novo three
copies in the cell so patients with Down
syndrome have a longer and longer life
expectancy now in the United States as
recently as 1983 the average life
expectancy was 25 and then in 2002 it
was 49 a lot of this came from better
standard therapies for a lot of the
complications of these children we have
to attend to their hearing loss and give
them hearing implants or hearing aids if
they're having a problem with hearing of
course we're gonna treat their
hypothyroidism aggressively one final
complication in adulthood I'd like to
mention is early onset Alzheimer's
disease this is very prevalent and
happens in about 10% of 50 year olds
with trisomy 21 and even 75% of 60 year
olds with trisomy 21 it happens because
the amyloid precursor protein gene or a
PP is actually on the 21st chromosome so
they have a genetic predisposition to
early onset Alzheimer's
before I close I want to say something
in general about patients with
Alzheimer's these children tend to be
extremely happy extremely loving and
wonderful to parent they live amazing
and positive lives and they have great
attitudes it's really interesting that
these children live such happy lives one
wonders if in many ways it might be a
blessing for a child to have trisomy 21
it's something we should support these
families we should give them all the
medical support they need and the social
support they need but recognize that
these children are valuable contributors
to society they're wonderful kids thanks
for your time
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