USMLE® Step 2 style questions USMLE
A 7-year-old girl comes to the office with a one day history of increasing nausea, lethargy, and polyuria. Her serum creatinine is 3.0 mg/dL and serum calcium is 17 mg/dL. Physical examination shows “elfin” facies, short stature, and signs of intellectual disability, despite well-developed verbal skills for her age. She also seemed to be extremely comfortable and talkative around the office staff, whom she has never encountered prior to this visit. Echocardiogram shows supravalvular aortic stenosis. A standard Giemsa-banded karyotype reveals no visible abnormalities. Which of the following techniques is most appropriate in confirming the most likely diagnosis?
Williams syndrome, also known as Williams-Beuren syndrome, is named after Dr. J. C. P. Williams who first described it.
This is a chromosome disorder in which a small portion of chromosome 7 is deleted, which results in physical and developmental problems.
Now, our DNA is this humongous blueprint on how to make a human and it’s usually packaged up nicely into 46 chromosomes.
These 46 chromosomes come in 23 pairs - and each pair has one chromosome from each parent.
Now, the individual chromosomes are shaped like an “X” with two short arms and two long arms linked together in the center by a centromere.
These two short arms are also referred to as p arms from the French term “petit” meaning small.
What's more, the two long arms are also referred to as q arms, since 'q' follows 'p' in the alphabet.
In Williams syndrome, about 26 to 28 genes, including the elastin gene (ELN) on the long arm of chromosome 7 are missing due to a microdeletion.
In most cases, this occurs randomly during the formation of sex cells in one of the parents.
So a sperm cell or an ovum can potentially carry this microdeletion on the long arm of its chromosome 7 and go on to fuse with another sex cell - forming a new organism which has the microdeletion.
Rarely, the cause of Williams syndrome can also be inherited in an autosomal dominant fashion - so when a person with Williams syndrome has children, there is a 50% chance they’ll pass down their own microdeletion to the offspring.
Now, the precise location of the microdeletion is at band 7q11.23, just like the directions to an address: 7 stands for chromosome 7, 'q' refers to the long arm, 11.23 refers to the specific region on the chromosome- and then it gets very specific: region 1, band 1, sub-band 2, sub-sub-band 3.
This section of DNA spans about 26 to 28 genes and 1.5 to 1.8 million base pairs - so this is considered a microdeletion, because we’re talking about less than 5 million base pairs.
Even though this region is pretty small, it codes for some very important genes, one of which is the elastin gene, which is responsible for the production of elastin protein which allows many tissues in the body to resume their shape after stretching or contracting.
So the symptoms of Williams syndrome are linked to connective tissue abnormalities resulting from these missing genes.
For example, the loss of the elastin gene leads to a broad forehead, flat nasal bridge, periorbital puffiness, short upturned nose, long medial cleft, full lips, and wide mouth that in combination give an "elfin" like appearance.
Other connective tissue abnormalities are the narrowing of major blood vessels, which predisposes to hypertension.
When the pulmonary arteries narrow, this causes pulmonary artery stenosis.
When the aorta narrows just above the aortic valve, this causes supravalvular aortic stenosis.