USMLE® Step 1 style questions USMLE
A 13-year-old girl comes to the office because she is concerned about not getting her first menstrual cycle. Her older sister had menarche at age 11. She states that she has also noticed that her voice has been getting deeper. Examination shows partial labial fusion, with clitoromegaly, and partially descended testes. Laboratory investigations show that the karyotype is 46 XY. Ultrasound scanning shows neither ovaries, nor a uterus. Which of the following best explains the direct cause of this patient’s condition?
Content Reviewers:Rishi Desai, MD, MPH
5α- reductase deficiency is a genetic disorder in which a protein called 5α reductase is defective or absent.
That’s an enzyme that converts the male hormone testosterone to its more potent form, called dihydrotestosterone.
One of the most important roles of dihydrotestosterone is to help male external genitalia develop in a male fetus.
Okay, normally, very early on in fetal life, male and female internal sex organs and external genitalia are undifferentiated and look identical.
Within the first few months of development, testes develop in the male fetus.
The testes start producing testosterone - a male steroid hormone that belongs to a class of hormones called androgens.
The testosterone gets released into the blood and a tiny fraction of it gets converted by 5α- reductase, which is mainly made in the skin of the genital area, into dihydrotestosterone.
Over time, dihydrotestosterone levels start rising and it affects undifferentiated genital structures.
Looking closely at these structures, at the top there’s the genital tubercle, which is a small projection.
Just below that, there's the urethral groove, which is the external opening of the urogenital sinus or the future urethra and bladder and is surrounded by the urethral folds and the labioscrotal swellings.
Now, once dihydrotestosterone reaches these structures, it makes the genital tubercle elongate into the phallus which will eventually be the penis.
The elongating genital tubercle pulls up the urethral folds which fuse in the midline, forming the spongy or penile urethra.
The tips of the urethral folds remain unfused and that forms the external urethral opening at the distal tip of the penis.
The labioscrotal swellings also fuse proximally to form the scrotum, which eventually houses the testes.
In females, the gonads develop into ovaries, which produce very low levels of androgens, so the genital tubercle remains small, forming the clitoris and the urethral folds and labioscrotal swellings remain unfused or separate, surrounding the opening of the vagina.
This process is usually complete by month four of fetal development.
In 5α- reductase deficiency there’s a mutation in the gene SRD5A2 and that reduces the amount of 5α- reductase enzyme that’s made.
The condition is inherited in an autosomal recessive but sex-limited pattern.
This means that for the disease to appear, both copies of the gene have to be mutated and the individual has to be genetically male, with one X and one Y chromosome in each cell, since dihydrotestosterone has no role in the development of genetically female individuals, with two X chromosomes in each cell.
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