Down syndrome is an autosomal trisomy disorder associated with increased nuchal and a hypoplastic nasal bone in a first trimester ultrasound.
USMLE® Step 1 style questions USMLE
USMLE® Step 2 style questions USMLE
A 39-year-old woman, gravida 4, para 3, comes to the office for an evaluation at 20 weeks' gestation. Given her advanced maternal age, she is concerned about having a child with a chromosomal abnormality. Which of the following results on the quadruple screening test are most likely to raise suspicion of Down syndrome in the fetus?
As you’re probably well-aware, our DNA is like this humongous blueprint of information on how to make a human.
Usually this massive document is packaged up nicely into a storage bin called a chromosome.
Actually, usually we have 46 chromosomes that we use to neatly organize all our information, depending on how you define organize.
Each of the 46 chromosomes is actually part of a pair of chromosomes, since you get one from each parent, so 23 pairs.
If you wanted to make another human, first you’d have to find someone that feels the same way, and then you both contribute half of your chromosomes, so one from each pair, right? Fifty-fifty.
Now, what if someone contributes one too many? Say Dad contributes 23 and Mom contributes 24, is that possible?
Yes, and it’s the basis of one of the most common chromosomal disorders—Down Syndrome.
Someone with Down syndrome has 47 chromosomes instead of 46, specifically they have an extra copy of chromosome 21, so instead of two, they have three, so Down Syndrome’s also known as trisomy 21, in other words, “three chromosome 21s”.
Alright, so in order to package up half the chromosomes into either a sperm cell or an egg cell, you actually start with a single cell that has 46 chromosomes, let’s just say we’re making an egg cell for the mother, I’m just going to show one pair of chromosomes, but remember that all 23 pairs do this.
So the process of meiosis starts, which is what produces our sex cells, and the chromosomes replicate, and so now they’re sort of shaped like an ‘X’—even though there are two copies of DNA here, we still say it’s one chromosome since they’re hooked together in the middle by this thing called a centromere.
OK then the cell splits in two, and pulls apart the paired chromosomes, so in each of these cells you’ve now got 23 chromosomes.
Now the two copies of the chromosome get pulled apart, and the cells split again, which means four cells, each still with 23 chromosomes.
Now these are ready to pair up with a sperm cell from dad that has 23 chromosomes as well, totaling to 46 chromosomes, and voila–nine months down the road you’ve got yourself a baby.
Now, with Down Syndrome or trisomy 21, a process called nondisjunction accounts for about 95% of cases.
Non-disjunction means the chromosomes don’t split apart.
If the chromosomes in this first step don’t split apart, then one cell ends up with both chromosomes and the other gets none.
Then the final result is 2 cells with an extra chromosome, and two cells missing a chromosome.
Nondisjunction can also happen in the second step though, so first steps goes great, and both cells have a chromosome, but if they don’t split apart in the second step, then the final result is one cell with an extra chromosome, one cell missing chromosome, and two with the right number of chromosomes.
Now, if a sperm cell combines with any of these that have a duplicate of chromosome 21, then the combined cell will have one extra copy of chromosome 21, in other words, “three chromosome 21s”, or trisomy 21.
In case you were wondering, the sperm could also combine with these cells that have the missing chromosome, if that’s the case then there would be a total of only one chromosome 21, and we would call it monosomy 21.
In my example, we followed the egg cell from the mother, but this process could happen the opposite way where the sperm starts out with too many or too few copies of chromosome 21.
Apart from nondisjunction, Robertsonian translocation accounts for about 4% of trisomy 21 cases.
Translocation, in this case, is a fancy way of saying move from one place to another; so a part of one chromosome moves and switches places with a part from another chromosome.
In this case, the long arm of chromosome 21 translocates over to chromosome 14, and you end up with two hybrids, one with both long arms and one with both short arms.
This little guy with the short arms carries just a little bit of, usually nonessential genetic information, and is typically lost by the end of meiosis.
So there are a few ways this can go down, first, including the translocated chromosomes, they replicate, and now these could split into one with both normal chromosomes, and one with the long guy and short guy, in which case after splitting again you’d have two normal cells and two cells with a big guy, since we lost the little guy along the way.
So now contribute the other parents DNA, and you’ve got a two normal cases, and then these two cases are called “balanced carriers”, and we say it’s balanced because you’ve got both long arms, and so most of the genes are still here, kind of like a two-for-one deal.
K now let’s say the normal chromosome 14 ends up with the short, and normal chromosome 21 with the long.
Now you get two cells with the normal and long-arm, and two cells with the normal and short arm, which remember is usually lost.
So these ones have one extra chromosome 21, since the long arms carry most of the genetic material for both chromosomes 14 and 21, and these ones are missing chromosomes.
Now combine these with the other parent’s again, and you have trisomy 21 here, and monosomy 21 here, since it’s missing a chromosome 21.