Conditions · Metabolism (biochemistry)
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency !
An inherited disease in which the adrenal gland makes too little cortisol and aldosterone and too much androgen; it can cause severe newborn crises.
Updated 2026-11-01
Structures involved
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In biochemistry
- Adrenal cortisol synthesis: Step 4 · 21-Hydroxylase (CYP21A2)
- Adrenal enzymes and congenital adrenal hyperplasia
- 21-Hydroxylase (CYP21A2)
- Cortisol
- Aldosterone
- 17-Hydroxyprogesterone (17-OHP)
In embryology
- Adrenal gland: cortex from mesoderm, medulla from neural crest
- Androgens, diethylstilbestrol and other hormones
- Sex determination: SRY, anti-Müllerian hormone and testosterone
- External genitalia and their male–female homologues
- Differences of sex development: CAH, AIS and 5α-reductase
In the clinical exam
In physiology
Why it happens
What it is
An autosomal recessive disorder from CYP21A2 variants that lowers cortisol (and often aldosterone) and diverts precursors into androgens.
Who gets it
The classic form affects about 1 in 15,000 newborns and the non-classic form about 1 in 1,000 people; it causes about 95 % of congenital adrenal hyperplasia. Frequency varies between populations; no Colombian figures are cited here.
Causes
- Variants in both copies of CYP21A2 (chromosome 6p21.3)
- Recombination with the neighbouring pseudogene CYP21A1P (deletions and gene conversions)
- Autosomal recessive inheritance
Risk factors
- Carrier parents
- An affected sibling (25 % risk in each pregnancy)
- Consanguinity
Pathophysiology
21-Hydroxylase turns 17-hydroxyprogesterone into 11-deoxycortisol and progesterone into 11-deoxycorticosterone. Without it cortisol falls, the pituitary releases more ACTH and the cortex enlarges. The piled-up 17-hydroxyprogesterone is diverted by 17,20-lyase into androstenedione and testosterone, which virilise the external genitalia of a female fetus (uterus and ovaries are normal). In the salt-wasting form aldosterone is also missing: the kidney loses sodium and keeps potassium, and a crisis with dehydration and shock appears around the second week of life.
Classification
- Classic salt-wasting (the most severe)
- Classic simple virilising (enough aldosterone)
- Non-classic or late-onset (residual enzyme activity)
Symptoms and signs
- Ambiguous genitalia in newborn girls (clitoromegaly, fused labia)
- Vomiting, poor feeding and dehydration in the first weeks (salt-wasting)
- Pubic hair and fast growth in childhood, with advanced bone age
- Short final height
- In the non-classic form: hirsutism, acne and irregular cycles in adolescent girls and women
Diagnosis
- Clinical
- Suspected from ambiguous genitalia, a salt-wasting crisis in a boy with normal genitalia, or early pubarche; newborn screening finds many cases before symptoms.
- Tests
- Very high 17-hydroxyprogesterone (heel-prick screening; ACTH stimulation test in the non-classic form); low sodium and high potassium; high renin; low cortisol; high androstenedione; karyotype; CYP21A2 genetic testing.
- Imaging
- Pelvic ultrasound to confirm the uterus and ovaries; hand X-ray for bone age; ultrasound may show enlarged adrenals.
Treatment
- Medical
- Glucocorticoid replacement (hydrocortisone in childhood) and mineralocorticoid replacement with salt supplements in salt-wasting infants
- Acute
- In adrenal crisis: intravenous fluids with glucose and intravenous hydrocortisone
- Surgical
- Genital surgery in selected cases, decided by a multidisciplinary team with the family
- Follow-up
- Follow-up of growth, bone age, 17-hydroxyprogesterone and androstenedione; education on stress dosing during illness
Complications
- Adrenal crisis and newborn death if missed
- Short stature
- Infertility; testicular adrenal rest tumours
- Iatrogenic Cushing syndrome from overtreatment
Prognosis
With early diagnosis and lifelong treatment, life expectancy is near normal.
Prevention
- Newborn screening with 17-hydroxyprogesterone
- Genetic counselling for families with a case
Test yourself
Think of the answer, then tap the question to see it.
Which gene is altered in 21-hydroxylase deficiency?
CYP21A2, on chromosome 6, next to a pseudogene it recombines with.
Why are affected girls born with ambiguous genitalia but a normal uterus?
Adrenal androgens virilise the external genitalia; the internal female organs form normally because there are no testes or anti-Müllerian hormone.
Which electrolyte changes does the salt-wasting form cause?
Low sodium and high potassium from lack of aldosterone, with high renin.
Which marker is measured in newborn screening?
17-Hydroxyprogesterone.
Related conditions
- Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency
- Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency
- Adrenal insufficiency
- Polycystic ovary syndrome
Educational information, not medical advice. For any symptom, see a health professional.
Sources: 21-hydroxylase deficiency: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); CYP21A2 gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Congenital adrenal hyperplasia: MedlinePlus Medical Encyclopedia (MedlinePlus, US National Library of Medicine, 2026).
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