Congenital adrenal hyperplasia: three enzymes, three patterns
Congenital adrenal hyperplasia is one disease family with opposite blood pressures. Ask what piles up, what falls and where it spills to predict the pattern for each enzyme.
Predict the blood pressure, potassium and androgen effects of 21-hydroxylase, 11-beta-hydroxylase and 17-alpha-hydroxylase deficiency.
The short version
- Congenital adrenal hyperplasia is an autosomal recessive deficiency of one adrenal enzyme; low cortisol removes feedback, so ACTH rises and the adrenal glands enlarge.
- For every block ask three questions: what piles up, what falls, and where does the pile-up spill.
- Salt-wasting 21-hydroxylase deficiency lowers blood pressure; 11-beta and 17-alpha-hydroxylase deficiency raise it through deoxycorticosterone.
- Androgens are high in 21-hydroxylase and 11-beta-hydroxylase deficiency, and low in 17-alpha-hydroxylase deficiency.
- Markers: raised 17-hydroxyprogesterone for 21-hydroxylase, raised 11-deoxycortisol for 11-beta-hydroxylase.
Three patients with enlarged adrenal glands
Three patients have enlarged adrenal glands and a raised ACTH. One is limp and vomiting, with low blood pressure and a high potassium. One has high blood pressure and a low potassium. The third has high blood pressure, a low potassium, and never goes through puberty.
That is the same disease family with three different enzymes. This lesson on congenital adrenal hyperplasia shows how to tell them apart by predicting the blood pressure, potassium and androgen effects of each block.[1][7]
Congenital adrenal hyperplasia: low cortisol, high ACTH and three questions
Congenital adrenal hyperplasia means one enzyme of the adrenal steroid pathway is deficient from birth. It is inherited as an autosomal recessive trait.[1]
When the block lowers cortisol, the feedback is lost, so ACTH rises and the adrenal glands enlarge.[1][7]
- What piles up?The steroid just before the block accumulates.
- What falls?The hormones made after the block fall.
- Where does the pile-up spill?The precursors are diverted down whichever pathway is still open: towards androgens in 21- and 11-beta-hydroxylase deficiency, towards deoxycorticosterone in 17-alpha-hydroxylase deficiency.[1][7]
21-hydroxylase deficiency: salt wasting and virilised girls
21-hydroxylase deficiency accounts for about 95% of all cases.[2][5] It blocks progesterone becoming deoxycorticosterone, and 17-hydroxyprogesterone becoming 11-deoxycortisol.[2]
Cortisol falls, and in the severe salt-wasting form aldosterone falls too. 17-hydroxyprogesterone piles up and spills into androgens: girls are born with ambiguous genitalia, while boys look normal at birth.[1][2]
Without aldosterone the kidney wastes salt, giving low sodium, high potassium and low blood pressure, and in the severe form an adrenal crisis in early infancy.[2][4]
The marker is a raised 17-hydroxyprogesterone, which is what newborn screening measures.[2][5]
11-beta-hydroxylase deficiency: high blood pressure, low potassium
11-beta-hydroxylase deficiency is the second most common form. It blocks 11-deoxycortisol becoming cortisol, and deoxycorticosterone becoming corticosterone.[3]
Deoxycorticosterone is itself a mineralocorticoid, and it piles up because the high ACTH keeps driving the blocked pathway.[3]
The patient therefore holds salt, with high blood pressure, low potassium, alkalosis and a suppressed renin. The spill into androgens again causes virilisation.[3][7]
The clue is virilisation with high blood pressure; the high blood pressure is present in about two thirds of patients. The marker is a raised 11-deoxycortisol.[3]
17-alpha-hydroxylase deficiency: no androgens, no oestrogens
17-alpha-hydroxylase deficiency causes about 1% of cases.[7] This enzyme sits at the fork: without it, cortisol and the sex steroids both fall. The only open road leads to deoxycorticosterone and corticosterone.[7]
Deoxycorticosterone drives high blood pressure and a low potassium. Corticosterone has glucocorticoid activity, so there is usually no adrenal crisis.[7]
With no androgens or oestrogens, a genetic male has female-looking external genitalia, and a genetic female has no puberty and primary amenorrhoea.[7]
The pattern across the three enzymes
| Deficiency | Blood pressure | Potassium | Androgens | Marker or clue |
|---|---|---|---|---|
| 21-hydroxylase (salt-wasting form) | Low | High | High | Raised 17-hydroxyprogesterone |
| 11-beta-hydroxylase | High | Low | High | Raised 11-deoxycortisol |
| 17-alpha-hydroxylase | High | Low | Low | No androgens or oestrogens |
Eleven and seventeen raise blood pressure; salt-wasting twenty-one lowers it. Androgens are high in 21 and 11, and low in 17.[2][3][7]
Rarer blocks at the very start of the pathway, such as StAR or 3-beta-hydroxysteroid dehydrogenase, cut cortisol and aldosterone, so they can cause salt wasting, and boys are under-virilised.[6][7]
Practice question
Original · USMLE styleA 6-year-old boy is brought to the clinic because of pubic hair and penile enlargement over the past year. His testes are prepubertal in size, and his bone age is advanced. His blood pressure is 138/92 mm Hg. Serum potassium is 3.1 mEq/L and bicarbonate is 31 mEq/L. Plasma ACTH and serum testosterone are increased, serum cortisol is decreased, and plasma renin activity is suppressed.
Common questions
What is congenital adrenal hyperplasia?
It is an inherited, autosomal recessive deficiency of one adrenal steroid enzyme. Low cortisol removes feedback, so ACTH rises and the adrenal glands enlarge.
Which enzyme deficiency is the most common cause of congenital adrenal hyperplasia?
21-hydroxylase deficiency, about 95% of all cases. 11-beta-hydroxylase deficiency is the second most common form.
Why do 11-beta and 17-alpha-hydroxylase deficiency cause high blood pressure?
Deoxycorticosterone, a mineralocorticoid, piles up. It drives salt retention, high blood pressure, low potassium and suppressed renin.
Why does 21-hydroxylase deficiency cause low blood pressure?
In the severe salt-wasting form aldosterone falls, so the kidney wastes salt. This gives low sodium, high potassium and low blood pressure.
What does newborn screening measure for 21-hydroxylase deficiency?
A raised 17-hydroxyprogesterone, the steroid that piles up behind the block.
Transcript
Read the full narration, by chapter654 words
0:00Three patients, one enlarged adrenal gland
Three patients have enlarged adrenal glands and a raised ACTH. One is limp and vomiting, with low blood pressure and a high potassium. One has high blood pressure and a low potassium. The third has high blood pressure, a low potassium, and never goes through puberty. Same disease family,
0:19Three different enzymes, one question
three different enzymes. How do you tell them apart? Today: predict the blood pressure, potassium and androgen effects of 21 hydroxylase, 11 beta hydroxylase and 17 alpha hydroxylase deficiency. Last time we mapped the pathway.
0:35Congenital adrenal hyperplasia and the three questions for any block
Congenital adrenal hyperplasia means one of its enzymes is missing from birth, inherited as an autosomal recessive trait. When the block lowers cortisol, the feedback is lost, so ACTH rises and the adrenal glands enlarge. For every block, ask three questions. What piles up? What falls? Where does the pile-up spill?
1:0321-hydroxylase deficiency: salt wasting, virilised girls
Start with 21-hydroxylase deficiency, about 95% of all cases. It blocks progesterone becoming deoxycorticosterone, and 17-hydroxyprogesterone becoming 11-deoxycortisol. So cortisol falls, and in the severe salt-wasting form aldosterone falls too. 17-hydroxyprogesterone piles up and spills into androgens: girls are born with ambiguous genitalia, while boys look normal at birth. Without aldosterone the kidney wastes salt, giving low sodium, high potassium and low blood pressure, and in the severe form an adrenal crisis in early infancy. The marker is a raised 17-hydroxyprogesterone, which is what newborn screening measures. Next, 11 beta hydroxylase deficiency,
1:5211-beta-hydroxylase deficiency: high blood pressure, low potassium
the second most common form. It blocks 11-deoxycortisol becoming cortisol, and deoxycorticosterone becoming corticosterone. Deoxycorticosterone is itself a mineralocorticoid, and it piles up. The fasciculata makes some of it under ACTH, so the high ACTH keeps feeding the pile. So the patient holds salt, with high blood pressure, low potassium, alkalosis, and a suppressed renin. The spill into androgens again causes virilisation, so the clue is virilisation with high blood pressure, which is present in about two thirds. The marker is a raised 11-deoxycortisol.
2:3917-alpha-hydroxylase deficiency: no androgens, no oestrogens
Last, 17 alpha hydroxylase deficiency, about 1% of cases. This enzyme sits at the fork. Without it, cortisol and the sex steroids both fall. The only open road leads to deoxycorticosterone and corticosterone. Deoxycorticosterone drives high blood pressure and a low potassium. Corticosterone has glucocorticoid activity, so there is usually no adrenal crisis. With no androgens or oestrogens, a genetic male has female-looking external genitalia, and a genetic female has no puberty and primary amenorrhoea. The pattern: 11 and 17 raise blood
3:19The pattern across all three
pressure; salt-wasting 21 lowers it. Androgens are high in 21 and 11, and low in 17. Rarer blocks at the very start of the pathway, such as StAR or three beta hydroxysteroid dehydrogenase, cut cortisol and aldosterone, so they can cause salt wasting, and boys are under-virilised.
3:45Your turn: a practice question
Your turn. A 6-year-old boy has had pubic hair and penile enlargement for a year. His testes are prepubertal, and his bone age is advanced. His blood pressure is 138 over 92. Potassium is 3.1, and bicarbonate is 31. ACTH and testosterone are high, cortisol is low, and plasma renin activity is suppressed. Which of the following deficiencies is most likely? A, three beta hydroxysteroid dehydrogenase. B, 17 alpha hydroxylase. C, 21-hydroxylase. D, steroidogenic acute regulatory protein. E, 11 beta hydroxylase. Pause here and decide.
4:37Ruling out the options one at a time
A is out: that block leaves boys under-virilised, and it can waste salt. B is out: androgens would be low, not high. C is out: 21 deficiency never pairs high blood pressure with low potassium; the salt-wasting form gives low blood pressure and high potassium. D is out: lipoid hyperplasia lowers every steroid and causes salt wasting. So the answer is E.
5:04The answer and why
Eleven beta hydroxylase deficiency piles up deoxycorticosterone, causing high blood pressure, low potassium and low renin, and spills into androgens.
5:17Recap pocket card and next lesson
Three things to keep. One: ask what piles up, what falls, and where it spills. Two: salt-wasting 21 lowers blood pressure; 11 and 17 raise it. Three: androgens are high in 21 and 11, and low in 17. Next, Cushing syndrome, and how to localise its source.
Sources
Numbers in the text, e.g. [1], point here- MSD Manual Professional Version. Overview of Congenital Adrenal Hyperplasia. msdmanuals.com/professional/pediatrics/endocrine-disorders-in-children/overview-of-congenital-adrenal-hyperplasia
- MSD Manual Professional Version. CAH due to 21-hydroxylase deficiency. msdmanuals.com/professional/pediatrics/endocrine-disorders-in-children/congenital-adrenal-hyperplasia-caused-by-21-hydroxylase-deficiency
- MSD Manual Professional Version. CAH due to 11 beta-hydroxylase deficiency. msdmanuals.com/professional/pediatrics/endocrine-disorders-in-children/congenital-adrenal-hyperplasia-caused-by-11beta-hydroxylase-deficiency
- MSD Manual Professional Version. Primary Adrenal Insufficiency. msdmanuals.com/professional/endocrine-and-metabolic-disorders/adrenal-disorders/primary-adrenal-insufficiency-addison-disease
- Endocrine Society CAH guideline summary, 2010. pmc.ncbi.nlm.nih.gov/articles/PMC2963799/
- Kater CE. Arch Endocrinol Metab 2022 (adrenal cortex zones and steroidogenesis). pmc.ncbi.nlm.nih.gov/articles/PMC9991025/
- Open-access CAH literature (PMC): pmc.ncbi.nlm.nih.gov/articles/PMC13354034/ · pmc.ncbi.nlm.nih.gov/articles/PMC13210843/ · pmc.ncbi.nlm.nih.gov/articles/PMC11730102/ · pmc.ncbi.nlm.nih.gov/articles/PMC12602608/ · pmc.ncbi.nlm.nih.gov/articles/PMC13346833/ · pmc.ncbi.nlm.nih.gov/articles/PMC10036490/ · pmc.ncbi.nlm.nih.gov/articles/PMC13533673/ · pmc.ncbi.nlm.nih.gov/articles/PMC13263069/
The practice question is original and its patient is synthetic. Every fact is checked against the sources above in independent accuracy reviews. Always follow your local guidelines and your own laboratory’s ranges.
Image credits. Illustrations: Servier Medical Art (smart.servier.com), CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/), adapted (cropped, recoloured, outlined, resized): newborn, child, teenager, blood pressure cuff (sphygmomanometer), kidney with adrenal gland, pituitary gland. The pathway boards, bars, dials, cards and all handwriting are drawn in code (original). No AI-generated teaching images.
Corrections. None so far. Spotted an error? Email info@medservatory.com with the lesson code MS-S1-ENDO-006.
For exam study only, not medical advice. Read the medical disclaimer.
In this series
Playlist on YouTube- EP 01Hypothalamic-pituitary axes and feedback: primary, secondary, tertiary5:05
- EP 02Primary vs secondary endocrine disorders: paired hormone levels5:13
- EP 03Insulin secretion in the beta cell: from glucose to granule5:06
- EP 04Insulin vs glucagon signalling: receptors and effects5:19
- EP 05DKA vs HHS pathophysiology: why only one makes acid5:58
- EP 06Diabetes drugs by mechanism: where each class acts5:58
- EP 07Thyroid hormone synthesis, step by step5:14
- EP 08Calcium homeostasis: PTH, vitamin D and calcitonin5:28
- EP 09Adrenal steroidogenesis: zones, enzymes and the 17α-hydroxylase fork5:29
- EP 10Congenital adrenal hyperplasia: three enzymes, three patterns5:44
- EP 11Cushing syndrome: the dexamethasone suppression test and ACTH5:29
- EP 12Primary hyperaldosteronism: high aldosterone, low renin5:27
- EP 13SIADH vs diabetes insipidus: central vs nephrogenic DI5:44
- EP 14MEN1, MEN2A and MEN2B: match the gene to its tumours5:13