ITB Principles For The USMLE, COMLEX, And Shelf Exams: Follow The Pathophysiology Part 2
Here’s part 2 of the question dissection promised in my article “How to Use a Pea Plant to Increase your USMLE, COMLEX and Shelf Exam Scores” over at SDN. See part 1 here.
To return to the question in its entirety.
A newborn infant is examined in the delivery room and found to have ambiguous genitalia. Non-invasive prenatal testing was performed at 11 weeks gestational age and the results showed a karyotype consistent with a female fetus. Physical examination of the infant shows clitoromegaly and partial fusion of the labial folds. The infant appears otherwise well with normal vital signs. Which of the following is the most likely mechanism involved?
A. Androgen receptor defect
B. Complete gonadal dysgenesis
C. Deficiency of 21-hydroxylase
D. Ovarian failure
E. Prenatal androgen exposure
Let’s take them one by one.
Choice A. Androgen receptor defect
What would happen if a female with an X,X karyotype had an androgen receptor defect? Of course, females have androgens and androgen receptors. But would the inability to “process” androgens in a female lead to ambiguous genitalia? That is, theoretically, if a female had no androgens during organogenesis what would happen to her genitalia? Are androgens necessary for the development of the normal vulvar architecture? Likely, even if you remember, nothing else about embryology, you know that androgens like testosterone aren’t necessary for the normal development of female external genitalia. So an X,X female without an androgen receptor, would not have ambiguous genitalia. She’d have normal external genital. So let’s cross out choice A for now.
Choice B. Complete gonadal dysgenesis
What do you know about X,X females’ gonadal development? In the normal process of development, the unique karyotype of the sex chromosome determines differentiation of the gonads. Furthermore, “female” differentiation is the default pathway. You’ve probably heard the oversimplification “we all start out as females.” Anatomically, the embryo is sexually undifferentiated until about week 7 after fertilization. Around this time, during normal development, if there are two X chromosomes you get ovaries, but if you have one X chromosome and one Y chromosome the undifferentiated gonads become testes. But if the hormones of either gonad are not there or can’t do their job, the default pathway will take over and will result in an external appearance that looks female. At this point, you probably can conclude that—absent some additional factor besides complete gonadal dysgenesis—a normal female karyotype, with two X,X chromosomes, is incompatible with ambiguous genitalia. Scratch off choice B.
Choice C. Deficiency of 21-hydroxylase
Steroidogenesis. Our friend. At this point, if you concluded from reading the vignette alone that congenital adrenal hyperplasia was the most likely diagnosis described in the question stem and you remember that 21-hydroxylase deficiency causes CAH, on test day, you can click choice C and be done. Move on to the next question and don’t look back. Trust your instincts and what you know. If not, don’t fret.
Steroidogenesis is an incredibly complex topic. But if you recall from my first article, I argued that you could get by with just knowing six things about it. For our present purpose, points 3 and 6 are the most important facts to remember.
- 21-Hydroxylase converts progesterones (progesterone and 17a-hydroxyprogesterone) into steroids with weak mineralocorticoid and glucocorticoid activity.
- These weak steroids become the glucocorticoid, cortisol, and the quintessential mineralocorticoid, aldosterone.
- Deficiency in 21-Hydroxylase accounts for 90 percent of cases of congenital adrenal hyperplasia
- Defective enzymes lead to a build up in precursor substances and a decrease in downstream substances (the molecular basis for the clinical manifestations of diseases affecting this pathway). Deficient 21-Hydroxylase means no mineralocorticoid or corticosteroid activity but increased sex steroid (androgen and estrogen) activity.
- Without mineralocorticoids a person will not be able to take up Na+ and excrete K+ and without corticosteroids, gluconeogenesis suffers.
- Excessive androgens (androstenedione and testosterone) as in the case of 21-hydroxylase deficiency will virilize a female fetus due to the extra “male” sex hormones. She will likewise suffer from hyponatremia and hyperkalemia (because of absent aldosterone) and hypoglycemia (from absent cortisol). A male fetus will not suffer from ambiguous genitalia, but will have the metabolic derangements.
What do extra androgens do to the external genitalia of an X,X female? The presence of androgens will stimulate the sexually undifferentiated embryo’s external genitalia into a more “male appearance.” If the karyotype is X,Y the testes will produce androgens to differentiate the labial scrotal folds (common structure for both sexes prior to around 7 weeks of development) into the scrotum and will cause the phallus (another common structure) to elongate into the penis. The testes will also produce mullerian inhibiting substance which causes regression of the paramesonephric ducts that serve as the rudimentary structures that would otherwise become the uterus, cervix, fallopian tubes, and upper vagina).
Now remember, in the absence of a Y chromosome (and therefore the testes’ production of testosterone) the phallus (also called the genital tubercle) will develop into a clitoris and the labioscrotal folds (also dubbed genital swellings) will become the labia majora. However, when there are excess androgens, the clitoris will elongate and the labioscrotal folds will become fused. The end result? A female fetus with ambiguous genitalia. So let’s keep this answer as a possibility.
Choice D. Ovarian failure
Ovarian failure is a generic term. But from our discussion of choice B, we know that in a normal female with an X, X karyotype, even when the ovaries fail to develop, the default pathway will take over and lead to female sexual differentiation. A fortiori, a derangement in the function of the ovaries, will lead to the same result. So ovarian failure won’t have an effect on the external genitalia’s appearance. By itself, therefore, ovarian failure won’t account for ambiguous genitalia.
Choice E. Prenatal androgen exposure
We know the presence of excess androgens around the time of sexual differentiation will cause ambiguous genitalia in a female fetus with an X,X karyotype. So why not pick this choice? Here’s where your clinical reasoning comes in.
There are a number of things the question writer could do to the vignette to make this question either easier or more difficult. Adding something about the infant having hypoglycemia (from deficient corticosteroids) or hyponatremia/hyperkalemia (from deficient mineralocorticoids) would make the diagnosis of CAH more obvious and the question “easier.” Adding a sentence about the mother’s prenatal use of anabolic steroids while training as a competitive bodybuilder prior to finding out she was pregnant, would make the question easier as well by providing info that would “rule in” choice E as a correct answer. See what I mean about pertinent positives having a tendency to clue you in to the correct answer?
There are two reasons I believe you should pick choice C over choice E on test day.
1) Overall, congenital adrenal hyperplasia is the most common disease of sexual differentiation and the most common cause of ambiguous genitalia.
2) In the absence of some detail in the vignette to help you rule in prenatal androgen exposure, you would not be able to rule in choice E as the cause of the sexual ambiguity.
So the ITB principle you want to remember while you’re studying is that when two or more answer choices can both lead to the similar (or same) “result” (ambiguous genitalia), you should pick the one that results from a derangement of a physiologic process.
You’d expect them to add something about exogenous androgens, if they wanted prenatal androgen exposure to be keyed as the correct answer. Note this only applies when more than one answer choice can lead to the same clinical picture. Sometimes one disease, medication, or other condition is well known and infamously causes a unique clinical syndrome or picture. And in those cases (for instance, thalidomide causing phocomelia), you’d want to pick the “notable” cause even if there are rare pathophysiologic causes of a similar clinical picture. This is because the examiners might want to test your understanding of some particular concept or principle (even if it’s encountered only rarely or as a matter of historical interest) and further wouldn’t expect a medical student to know extremely exceptional material which might be appropriate only for a resident or subspecialist in that field.
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