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Difficulty: HardEndocrine and Metabolic Mechanisms

Match each clinical and biochemical profile of a patient presenting with a disorder of sex development or steroidogenesis to its precise underlying enzymatic or molecular mechanism.

  • A 46,XX neonate presenting with virilized external genitalia, hyponatremia, hyperkalemia, elevated plasma renin activity, and markedly elevated 17-hydroxyprogesteroneDecreased activity of 21-hydroxylase (CYP21A2)
  • A 46,XX adolescent presenting with primary amenorrhea, lack of secondary sexual characteristics, hypertension, hypokalemia, and elevated serum deoxycorticosteroneDecreased activity of 17-alpha-hydroxylase (CYP17A1)
  • A 46,XY adolescent presenting with a female phenotype, primary amenorrhea, absent uterus on ultrasound, and serum testosterone levels in the normal male rangeLoss-of-function mutation in the nuclear androgen receptor (AR)
  • A 46,XY neonate presenting with ambiguous genitalia, descended testes, normal electrolytes, and a significantly elevated testosterone-to-dihydrotestosterone ratioDecreased activity of 5-alpha-reductase type 2 (SRD5A2)

Answer

Profile L1 matches 21-hydroxylase deficiency; Profile L2 matches 17-alpha-hydroxylase deficiency; Profile L3 matches androgen receptor mutation; Profile L4 matches 5-alpha-reductase type 2 deficiency.
Each profile perfectly aligns with the biochemical consequences of specific enzymatic or receptor defects in the endocrine pathways governing steroid hormone synthesis and action.

Step-by-Step Solution

1
Evaluate the first profile (46,XX with salt-wasting and virilization).
Identified as classic congenital adrenal hyperplasia.
Elevated 17-hydroxyprogesterone indicates a block at 21-hydroxylase, leading to absent mineralocorticoids and excess androgens.
2
Evaluate the second profile (46,XX with hypertension, hypokalemia, and delayed puberty).
Identified as 17-alpha-hydroxylase deficiency.
The block prevents sex hormone synthesis (delayed puberty) and shunts precursors to mineralocorticoids like deoxycorticosterone (hypertension, hypokalemia).
3
Evaluate the third profile (46,XY with female phenotype, absent uterus, normal male testosterone).
Identified as complete androgen insensitivity syndrome.
Target tissues do not respond to testosterone due to a mutated receptor. The testes produce anti-Müllerian hormone, leading to regression of Müllerian structures (no uterus).
4
Evaluate the fourth profile (46,XY with ambiguous genitalia and high T/DHT ratio).
Identified as 5-alpha-reductase type 2 deficiency.
The high testosterone-to-dihydrotestosterone ratio specifically points to the inability to convert testosterone to the more potent dihydrotestosterone required for male external genitalia development.

Key Concept

Steroidogenesis pathways and disorders of sex development (DSD)
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Topics

Endocrine and Metabolic Mechanisms

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