EndocrinologyTier 2Disease (DEADMAN)

Adrenal gland disorders - congenital adrenal hyperplasia

Description

Autosomal recessive defects of cortisol biosynthesis
- dec cortisol -> loss of negative feedback -> inc ACTH -> adrenal hyperplasia + accumulation of precursors above the block
Precursors are shunted into whichever pathway remains open - that shunt determines the entire phenotype

Enzyme defects

Enzyme (gene)	Freq	Androgens	Mineralocorticoid	Marker
21-hydroxylase (CYP21A2)	~95%	inc	dec -> salt wasting	inc 17-OHP
11beta-hydroxylase (CYP11B1)	~5%	inc	inc DOC -> hypertension, hypokalaemia	inc 11-deoxycortisol, inc DOC
17alpha-hydroxylase (CYP17A1)	Rare	dec	inc DOC -> hypertension	inc DOC, inc corticosterone
3beta-HSD2	Rare	inc DHEA (weak)	dec	inc 17-preg
StAR / lipoid	Rare	dec (all)	dec	All steroids low

*The two hypertensive forms (11beta and 17alpha) are the exam trap* - CAH with hypertension and hypokalaemia, not salt wasting

21-hydroxylase phenotypes

Classical salt-wasting (~70% of classical) - <1% enzyme activity. Neonatal crisis + virilisation
Classical simple virilising (~30%) - 1-2% activity. Virilisation without salt loss
Non-classical (late-onset) - 20-50% activity. Presents in adolescence/adulthood as a PCOS mimic

Epidemiology

Classical 21-hydroxylase deficiency 1:14,000-1:18,000 births; carrier ~1:60
Non-classical much commoner - up to 1:1000 in general populations, 1:27 in Ashkenazi Jews, high in Hispanic and Mediterranean groups
On the Australian newborn bloodspot screening panel (17-OHP)
11beta-hydroxylase deficiency clusters in Moroccan Jewish populations

Aetiopathogenesis

CYP21A2 on 6p21.3 within the HLA class III region, adjacent to the CYP21A1P pseudogene
- Most mutations are gene conversions or deletions arising from misalignment with the pseudogene
- Genotype predicts phenotype well - the less severely affected allele determines severity
21-hydroxylase converts
- 17-OHP -> 11-deoxycortisol -> cortisol
- Progesterone -> DOC -> aldosterone
Block -> 17-OHP accumulates -> diverted through 17,20-lyase into androstenedione -> testosterone
- Also a "backdoor" pathway direct to DHT
Aldosterone deficiency -> Na loss, K retention, volume depletion, inc renin

Developmental consequences

External genitalia differentiate at 8-10 weeks' gestation, after the fetal adrenal begins secreting cortisol
- Androgen excess in that window virilises a 46,XX fetus - clitoromegaly, labial fusion, common urogenital sinus
- *Internal organs are normal - ovaries make no AMH, so Mullerian structures persist* (uterus and tubes present)
Male fetuses are not virilised in utero beyond normal; placental aromatase protects against maternal androgen
46,XY infants therefore look normal at birth -> present in salt-wasting crisis at 1-3 weeks, easily missed

Diagnosis

Classical, neonatal

Salt-wasting crisis at 7-21 days: vomiting, poor feeding, weight loss, shock
- Hyponatraemia, hyperkalaemia, metabolic acidosis, hypoglycaemia, raised renin
Ambiguous genitalia in 46,XX; hyperpigmentation (inc POMC/ACTH)
Biochemistry: low cortisol, high ACTH, 17-OHP markedly raised (typically >30 nmol/L), high androstenedione, high renin, low aldosterone
Karyotype/QF-PCR, pelvic ultrasound, urgent electrolytes
17-OHP is high in normal newborns for the first 48h and in prematurity/illness - repeat, do not act on a single early sample

Non-classical

Presents like PCOS: hirsutism, acne, oligomenorrhoea, infertility, premature pubarche
In boys: early pubic/axillary hair, acne, phallic growth, advanced bone age with prepubertal testes
- *Small testes with virilisation = peripheral androgen source, not central precocious puberty* - the single most useful examination finding
Early-morning follicular-phase 17-OHP is the screen; often normal, so a normal random level does not exclude it
Confirm with a 250 microgram Synacthen test: 17-OHP at 0 and 60 minutes
- Stimulated 17-OHP >30 nmol/L -> classical; 10-30 nmol/L -> non-classical range
CYP21A2 genotyping to confirm and for genetic counselling

Monitoring markers

Androstenedione and testosterone (best), renin (mineralocorticoid adequacy), growth velocity and bone age in children
*Do not titrate to a normal 17-OHP* - normalising it requires supraphysiological glucocorticoid and causes Cushing

Management

Acute adrenal crisis

Hydrocortisone 50-100 mg/m2 IV (adult 100 mg) immediately, then infusion; 0.9% saline + glucose; treat hyperkalaemia
Do not wait for confirmatory results

Chronic replacement - the dual objective

Replace cortisol and suppress ACTH-driven adrenal androgen output. These two goals conflict - that conflict is the whole problem

Glucocorticoid
- Children: hydrocortisone 10-15 mg/m2/day in 3 divided doses - shortest-acting agent, to protect growth
- Adults: hydrocortisone, or prednisolone/dexamethasone once growth is complete (better androgen suppression, worse metabolic cost)
- Modified-release hydrocortisone more closely reproduces the early-morning ACTH surge
Mineralocorticoid (salt-wasting): fludrocortisone 50-200 microg/day; sodium chloride supplements in infancy
- Titrate to BP, renin and electrolytes
Stress dosing, sick-day rules, parenteral hydrocortisone at home, medical alert identification - in everyone
Crinecerfont - a genuine change in the field
- Selective CRF-1 receptor antagonist: dec pituitary ACTH -> dec adrenal androgen, without using supraphysiological steroid
- First new mechanism in ~70 years; enables reduction to physiological glucocorticoid doses in ~70% at 2 years
- Approved in the US for classical CAH aged >=4y; not yet TGA-registered in Australia
- Tildacerfont is a second CRF-1 antagonist still in development

Non-classical CAH

*Most need no glucocorticoid* - treat the presenting problem
- Hirsutism/acne/irregular cycles -> COCP +/- antiandrogen, as for PCOS
- Infertility or unacceptable symptoms -> low-dose glucocorticoid (prednisolone at night, or hydrocortisone)
Stress dosing only if a Synacthen test shows an inadequate cortisol response

Fertility and pregnancy

Women: androgen and progesterone excess impair conception; optimise control, switch to a non-placenta-crossing steroid (hydrocortisone or prednisolone) - not dexamethasone**
Men: testicular adrenal rest tumours (TART) cause obstructive infertility - ultrasound surveillance; they shrink with better ACTH suppression
Prenatal dexamethasone to prevent virilisation of an affected female fetus is experimental and not recommended outside a research protocol

Surgical

Feminising genitoplasty in 46,XX: timing is contested - increasingly deferred, multidisciplinary DSD team, informed by patient advocacy

Associations

Adrenal rest tissue - testicular (TART) and ovarian; mimics tumour, causes infertility
Adrenal myelolipoma - large, fat-containing, from chronic ACTH drive
Reduced final adult height (androgen-driven early fusion and glucocorticoid over-treatment)
Metabolic: obesity, insulin resistance, hypertension, dyslipidaemia, osteoporosis - largely iatrogenic
Non-classical CAH is a differential of PCOS and of premature pubarche
11beta and 17alpha forms - a cause of hypertension with hypokalaemia and suppressed renin in the young
Gender identity and psychosexual issues in virilised 46,XX individuals

Natural history & complications

Untreated classical salt-wasting -> death in the neonatal period; screening exists for this reason
Untreated simple virilising -> rapid childhood growth, advanced bone age, early epiphyseal fusion -> short adult stature, precocious pseudopuberty
- Long-standing androgen exposure can trigger secondary central precocious puberty once the axis matures
Adult outcomes are dominated by the treatment, not the disease: iatrogenic Cushing, osteoporosis, metabolic syndrome
Fertility reduced in both sexes; better with modern control
Lifelong specialist follow-up; adrenal crisis remains the leading preventable cause of death
Non-classical CAH does not cause adrenal crisis under normal circumstances and has a normal lifespan

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