Paediatrics chapters
Congenital adrenal hyperplasia
The inherited block in adrenal steroid synthesis that causes ambiguous genitalia in girls and salt-losing crises in newborns: enzyme forms, diagnosis with 17-hydroxyprogesterone, prenatal diagnosis, lifelong steroid treatment and outcome.
- CAH is an autosomal recessive defect of cortisol synthesis; low cortisol raises ACTH, the adrenals enlarge and precursors spill into androgens. 21-hydroxylase deficiency causes about 90 to 95%.
- Girls are born with ambiguous genitalia (normal uterus and ovaries); boys look normal; about three-quarters also lack aldosterone and present in the first 1 to 2 weeks with a salt-losing crisis: vomiting, dehydration, low sodium, high potassium, acidosis, hypoglycaemia, shock.
- Diagnosis: very high 17-hydroxyprogesterone, high renin, karyotype; treatment is lifelong hydrocortisone (plus fludrocortisone and salt for salt-losers), stress doses in illness, and surgery for genitalia when indicated.
On this page
Overview
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders in which an enzyme needed to make cortisol is missing. Low cortisol removes feedback, so ACTH rises, the adrenal glands become hyperplastic, and steroid precursors are pushed down the androgen pathway. The result depends on the enzyme: virilisation of girls, salt-wasting shock in newborns, or hypertension. It is the commonest cause of ambiguous genitalia in a genetic female and a classic cause of collapse in the second week of life.
Pathophysiology
The adrenal cortex has three zones:
| Zone | Main product |
|---|---|
| Glomerulosa (outer) | Aldosterone (mineralocorticoid) |
| Fasciculata (middle) | Cortisol (glucocorticoid) |
| Reticularis (inner) | Adrenal androgens (DHEA, androstenedione) |
In 21-hydroxylase deficiency:
- 17-hydroxyprogesterone (17-OHP) cannot be converted to 11-deoxycortisol → low cortisol.
- Progesterone cannot become deoxycorticosterone → low aldosterone (in the salt-losing form).
- Low cortisol → high ACTH → adrenal hyperplasia; the build-up of 17-OHP is diverted to androgens (androstenedione, testosterone).
- High ACTH also causes pigmentation of the genital skin and nipples.
Precursors before the block rise; hormones after the block fall. In 21-hydroxylase deficiency, 17-OHP and androgens are high; cortisol and aldosterone are low.
Types of CAH
| Enzyme defect | Frequency | Salt balance and BP | Genitalia |
|---|---|---|---|
| 21-hydroxylase (CYP21) | Commonest: about 90% (Akbar) to 95% (Nelson) | Salt loss in about three-quarters; normal BP | Virilised girls; boys normal |
| 11-beta-hydroxylase | Next commonest (about 5%) | Salt retention, hypertension, hypokalaemia (excess deoxycorticosterone) | Virilised girls; boys normal |
| 3-beta-hydroxysteroid dehydrogenase | Rare | Salt loss | Both sexes ambiguous (virilised girls, under-virilised boys) |
| 17-alpha-hydroxylase | Rare | No salt loss; sodium high-normal, potassium low | Under-virilised boys; girls not virilised |
| Lipoid CAH (StAR protein defect) | Rare | Severe salt loss | Under-virilised boys |
"1-1 for high BP": 11-hydroxylase deficiency gives hypertension; 21 gives salt loss.
11-beta-hydroxylase deficiency is virilising like 21-hydroxylase, but causes hypertension and low potassium, not salt loss.
Epidemiology and genetics
- Autosomal recessive; the 21-hydroxylase gene lies on the short arm of chromosome 6.
- Classic 21-hydroxylase deficiency: about 1 in 15,000 births in many populations (Nelson). Non-classic (late-onset) disease is much commoner, up to 1 in 50 in some groups.
- Akbar: about 70% salt-losing and 30% simple virilising; Nelson: aldosterone deficiency in about 75%.
Clinical features
1. Classic salt-losing 21-hydroxylase deficiency
Girls
- Ambiguous genitalia at birth: from mild clitoromegaly to complete fusion of the labioscrotal folds with a phallus-like clitoris.
- Uterus, tubes and ovaries are normal (androgens do not affect them).
- The genital ambiguity often leads to early diagnosis before a crisis.
Boys
- Normal genitalia at birth (perhaps subtle scrotal pigmentation), so the diagnosis is easily missed.
- Present with a salt-losing crisis, usually in the first 1 to 2 weeks (Akbar: about 10 to 14 days; Nelson: electrolytes change from about day 5 to 7).
Salt-losing (adrenal) crisis
- Poor feeding, vomiting, weight loss, dehydration.
- Hyponatraemia, hyperkalaemia, metabolic acidosis, hypoglycaemia, raised urea.
- Hypotension and shock; death if untreated.
A vomiting, dehydrated baby boy in the second week may be thought to have pyloric stenosis. Pyloric stenosis gives hypochloraemic alkalosis with normal or low potassium; salt-losing CAH gives hyponatraemia, hyperkalaemia and acidosis.
Every baby with ambiguous genitalia needs urgent electrolytes and assessment for salt loss, because salt-losing and simple virilising forms cannot be told apart clinically at birth.
2. Simple virilising 21-hydroxylase deficiency
- No salt loss (enough aldosterone).
- Girls: ambiguous genitalia at birth.
- Both sexes in childhood: early pubic hair (often before 2 years), phallic enlargement, acne, deep voice, rapid growth and muscular build, advanced bone age (peripheral precocious puberty).
- Tall child, short adult: early epiphyseal fusion reduces final height.
3. Non-classic (late-onset) CAH
- Mild enzyme defect; normal genitalia at birth.
- Presents in later childhood or adolescence with premature pubic hair, acne, hirsutism, and in girls irregular periods or amenorrhoea; can mimic polycystic ovary syndrome.
Confirmatory investigations
| Test | Finding (21-hydroxylase deficiency) |
|---|---|
| Serum 17-hydroxyprogesterone | Markedly raised (100 to 1,000 times normal in newborns); diagnostic |
| ACTH stimulation test with 17-OHP | Exaggerated rise; needed to diagnose non-classic CAH |
| Serum electrolytes | Low Na, high K, acidosis (salt-losers) |
| Plasma renin activity | High in salt-losers; aldosterone low |
| Cortisol | Low or undetectable |
| Androstenedione, testosterone | Raised |
| ACTH | Raised (not diagnostic alone) |
| Urinary 17-ketosteroids | Raised |
| Blood glucose | Low in crisis |
| Karyotype (and buccal smear for Barr bodies) | Confirms genetic sex (46,XX in a virilised girl) |
| Pelvic ultrasound | Uterus and ovaries present in girls; enlarged adrenals |
| Genitogram or contrast study | Internal anatomy before surgery |
- In 11-beta-hydroxylase deficiency: 11-deoxycortisol and deoxycorticosterone raised, potassium low.
- Measure the precursor just before the suspected block.
17-hydroxyprogesterone is the key diagnostic test; renin and electrolytes show whether the child is a salt-loser.
Prenatal diagnosis
Indication: a family with a previously affected child (both parents are carriers; each pregnancy has a 1 in 4 risk).
Principles
- Identify the CYP21 mutation in the affected child first.
- In the next pregnancy, test fetal DNA by chorionic villus sampling (first trimester) or amniocentesis for fetal sex and the CYP21 gene.
Prenatal treatment
- Dexamethasone (crosses the placenta) given to the mother early in pregnancy suppresses fetal ACTH and reduces virilisation of an affected female fetus.
- It must start before the diagnosis is known; it is stopped if the fetus is male or unaffected.
- Nelson notes this remains controversial.
Both parents carriers (autosomal recessive)
Affected chance per pregnancy = 1/2 × 1/2 = 1/4
Chance that a fetus is both female and affected = 1/4 × 1/2 = 1/8, so only 1 in 8 pregnancies started on dexamethasone actually benefits
Management
Goals: replace missing hormones, suppress excess ACTH and androgens, and achieve normal growth, puberty, sexual function and fertility.
Acute salt-losing crisis
- Take blood first (electrolytes, glucose, 17-OHP, cortisol, renin) but do not delay treatment.
- IV fluids: 0.9% saline with 5% dextrose to correct hypovolaemia, hyponatraemia and hypoglycaemia.
- Hydrocortisone in high doses: Akbar gives 30 to 50 mg/m2/day in 3 to 4 divided doses for the CAH crisis (and, for adrenal crisis generally, an initial IV dose of 50 mg/m2 followed by 12.5 mg/m2 every 4 to 6 hours).
- Treat dangerous hyperkalaemia if needed (calcium, bicarbonate, glucose and insulin, potassium-binding resin).
- Once stable and feeding, start fludrocortisone and taper hydrocortisone to maintenance.
Maintenance (lifelong in classic CAH)
| Drug | Dose | Purpose |
|---|---|---|
| Hydrocortisone (oral) | Nelson: about 10 to 15 mg/m2/day in 3 doses; Akbar: 15 to 20 mg/m2/day | Replace cortisol and suppress ACTH and androgens |
| Fludrocortisone (salt-losers) | Nelson: 0.1 to 0.2 mg/day; Akbar: 0.05 to 0.15 mg/day | Replace aldosterone |
| Sodium chloride | Akbar: 1 to 3 g/day; Nelson: often needed in infancy and early childhood | Extra sodium for salt-losers |
- Use the smallest glucocorticoid dose that suppresses the adrenal; Akbar suggests giving a larger share of the dose at night to blunt the early-morning ACTH surge.
- Stress dosing: increase glucocorticoid about 2 to 3 times (Nelson: three times) during fever, infection or surgery; give intramuscular hydrocortisone if the child is vomiting or very ill.
- Parents are taught when and how to give stress doses.
Monitoring
| Parameter | Purpose |
|---|---|
| 17-OHP and androstenedione (plasma or saliva) | Adequacy of glucocorticoid |
| Plasma renin activity, sodium, potassium, BP | Adequacy of mineralocorticoid (excess gives hypertension) |
| Height velocity and bone age | Best overall guide to correct dosing |
| Over-treatment | Under-treatment |
|---|---|
| Cushingoid features, obesity, growth stunting | Progressive virilisation, fast growth, advanced bone age, early puberty, short final height |
Surgery and support
- Feminising genital surgery (clitoral reduction, vaginoplasty) for virilised girls; timing is debated, with some advising waiting until the child can take part in decisions.
- Psychological support, genetic counselling, and a team approach (endocrinologist, surgeon, psychologist).
Prognosis by subtype, severity and timing
| Situation | Outlook |
|---|---|
| Early diagnosis, good adherence | Normal height, puberty, sexual function and fertility are possible |
| Salt-losing form, missed in a boy | Risk of death from adrenal crisis in the neonatal period |
| Salt-losing form, females | Fertility may be reduced; possible problems with menstrual regularity and vaginal reconstruction |
| Salt-losing form, males | Fertility usually normal |
| Simple virilising form, treated | Fertility unaffected in both sexes |
| Late diagnosis or poor control | Short adult height (advanced bone age), precocious puberty, virilisation, infertility |
| Non-classic | Mild; treated if symptomatic |
- Treatment is lifelong in classic CAH.
Expect: autosomal recessive inheritance and the 21-hydroxylase gene on chromosome 6; 21-hydroxylase deficiency as 90 to 95% of cases; the ACTH-driven mechanism; ambiguous genitalia in a 46,XX baby with normal internal organs; a normal-looking boy in shock at 1 to 2 weeks with low sodium, high potassium, acidosis and hypoglycaemia; distinction from pyloric stenosis; raised 17-OHP as the diagnostic test; high renin; 11-beta-hydroxylase deficiency with hypertension and hypokalaemia; prenatal diagnosis by CVS or amniocentesis after an affected child and prenatal dexamethasone; IV saline, dextrose and hydrocortisone in crisis; maintenance hydrocortisone, fludrocortisone and salt; stress dosing; monitoring with 17-OHP, renin, growth and bone age; signs of over- and under-treatment; tall child, short adult.
Quick revision
- Autosomal recessive; cortisol low → ACTH high → hyperplasia → androgens.
- 21-hydroxylase 90 to 95%; about three-quarters salt-losing.
- Girls: ambiguous genitalia, normal uterus and ovaries; boys: normal then crisis.
- Crisis at 1 to 2 weeks: vomiting, shock, low Na, high K, acidosis, low glucose.
- Pyloric stenosis = alkalosis, low Cl, normal/low K.
- 17-OHP hugely raised; renin high; karyotype; pelvic ultrasound.
- 11-beta-hydroxylase: virilisation + hypertension + low K.
- Prenatal: CVS or amniocentesis after an affected sibling; dexamethasone early in pregnancy (controversial).
- Hydrocortisone lifelong; fludrocortisone and salt for salt-losers; triple dose when ill.
- Monitor 17-OHP, androstenedione, renin, growth, bone age.
Written by The House Job from standard references (Basis of Paediatrics by Pervez Akbar; Nelson Essentials of Paediatrics).
FAQ
Why do boys with salt-losing CAH present later than girls?
Their genitalia look normal, so nothing prompts testing at birth; they present with vomiting, dehydration and shock when salt loss becomes severe in the first 1 to 2 weeks.
Which single test confirms 21-hydroxylase deficiency?
Serum 17-hydroxyprogesterone, which is raised hundreds to thousands of times above normal in affected newborns; an ACTH stimulation test is used for milder late-onset forms.
Which type of CAH causes high blood pressure?
11-beta-hydroxylase deficiency, because the precursor deoxycorticosterone acts as a mineralocorticoid; it also virilises girls and lowers potassium.
Why is the steroid dose increased during illness?
The child cannot raise cortisol under stress, so without extra hydrocortisone (about two to three times the usual dose, or by injection if vomiting) an adrenal crisis can occur.