Congenital adrenal hyperplasia

• Congenital adrenal hyperplasia (CAH) is a family of inherited enzyme defects that block the normal production of cortisol in the adrenal gland; the commonest and most studied form is 21-hydroxylase deficiency.
• A blocked cortisol pathway shunts precursor steroids into androgen production, so affected people have cortisol deficiency together with androgen excess; the severity ranges from a life-threatening salt-wasting illness in newborns to a mild late-onset excess of androgens in adults.
• Classic 21-hydroxylase deficiency occurs in roughly 1 in 14,000 to 1 in 18,000 births worldwide, with higher rates in some isolated populations.^[1]
• Newborn screening by 17-hydroxyprogesterone and early treatment prevent neonatal death and genital ambiguity; later diagnosis is made by an early-morning 17-hydroxyprogesterone and, when needed, a cosyntropin stimulation test.
• Treatment is lifelong glucocorticoid replacement, plus mineralocorticoid and sodium in salt-wasting disease, stress doses for serious illness, surgical and psychosocial care for virilised females, and genetic counselling for families.

By the end of this page you should be able to:

1. Draw the adrenal steroidogenic pathway and predict which hormones rise and fall for 21-hydroxylase, 11-beta-hydroxylase and 17-alpha-hydroxylase deficiency.
2. Recognise classic salt-wasting and simple virilising disease in a newborn, and nonclassic disease in an adolescent or adult.
3. Plan newborn and post-infancy biochemical diagnosis, including cosyntropin stimulation and the role of genotyping.
4. Outline glucocorticoid, mineralocorticoid, stress-dose, surgical and psychosocial management across the lifespan.
5. Explain prenatal diagnosis and why prenatal dexamethasone is treated as experimental.
6. Adapt management in a low-resource setting.

CAH is not one disease but a group of autosomal recessive disorders in which an enzyme needed for cortisol synthesis in the adrenal cortex does not work fully. Cortisol is the main glucocorticoid from the adrenal zona fasciculata; aldosterone is the main mineralocorticoid from the zona glomerulosa; and androgens come mainly from the zona reticularis. A block at any step deprives the body of cortisol, drives ACTH up, hyperstimulates the gland, and overflows cortisol precursors into androgen (and sometimes mineralocorticoid) production. More than 95 percent of cases are caused by 21-hydroxylase deficiency; the remainder are rare forms, of which 11-beta-hydroxylase and 17-alpha-hydroxylase deficiency are the next most important to recognise because both cause hypertension rather than salt loss.^[1][2]

CAH is best understood as "cortisol block plus overflow". The clinical picture depends entirely on which enzyme is blocked and how completely:

• 21-hydroxylase deficiency (21-OHD) can present as the classic salt-wasting form, the classic simple virilising form, or the milder nonclassic (late-onset) form. In all three, cortisol precursors spill into androgen synthesis. In the classic salt-wasting form aldosterone is also deficient.
• 11-beta-hydroxylase deficiency (11-OHD) also produces cortisol deficiency and androgen excess, but the precursor deoxycorticosterone (DOC) acts as a mineralocorticoid, so patients more often have hypertension and hypokalaemia than salt wasting.
• 17-alpha-hydroxylase/17,20-lyase deficiency (17-OHD) removes cortisol and sex steroid synthesis; corticosterone takes over glucocorticoid action, DOC drives mineralocorticoid excess, and both sexes fail to enter puberty because androgens and oestrogens are not made.
• Rarer defects (3-beta-hydroxysteroid dehydrogenase, P450 oxidoreductase, lipoid CAH) also exist; their details are in the source.

This page concentrates on the three forms above, because they are the ones that dominate clinical practice and exams, and it fills in the rarer enzyme forms only in the steroid table.

Severity is described as "classic" (severe, present in infancy) or "nonclassic" (partial, present later). Genotype predicts phenotype only imperfectly, because most patients are compound heterozygotes carrying different mutations on each allele.^[1]

Classic 21-OHD occurs in roughly 1 in 14,000 to 1 in 18,000 births in most populations, with higher rates in some isolated or consanguineous communities.^[1] CAH is the most common cause of adrenal insufficiency in children.^[3]

Nonclassic 21-OHD is much more common: one recent genetic estimate gives an overall frequency near 1 in 200 in the general population, and up to 1 in 50 to 1 in 100 in populations with high consanguinity.^[1] 11-OHD is the second most common form overall, accounting for about 0.2 to 8 percent of all CAH, with the highest rates in the Middle East. 17-OHD is rare; it is the second most common form in Brazil.^[2]

About 75 percent of classic 21-OHD patients have the salt-wasting form. Without newborn screening, salt-wasting males in particular die in the first weeks of life from unrecognized adrenal crisis; males outnumber losses in unscreened populations precisely because females are brought to attention by genital ambiguity.^[1]

All classic forms are autosomal recessive. The commonest cause of 21-OHD is mutation in CYP21A2 on chromosome 6p21.3; large deletions and an intron-2 splicing mutation that abolish enzyme activity account for about half of classic alleles.^[1] The salt-wasting (P450c21 null) phenotype is matched by mutations that preserve about 1 to 2 percent of enzyme activity in simple virilising disease and 20 to 50 percent in nonclassic disease (Val281Leu being the commonest nonclassic allele).^[1]

Risk factors are essentially genetic: a previous affected child, known carrier status, and consanguinity. About 5 to 10 percent of salt-wasting 21-OHD patients also have a form of Ehlers-Danlos syndrome because the adjacent tenascin-X gene (TNXB) is deleted together with CYP21A2.^[1]

There is no modifiable environmental risk factor. 11-OHD is caused by mutations in CYP11B1; 17-OHD by mutations in CYP17A1.

Adrenal steroidogenesis begins when cholesterol is converted to pregnenolone by the cholesterol side-chain cleavage enzyme inside mitochondria; StAR protein acutely moves cholesterol into the mitochondrion. Pregnenolone then flows down three main branches, in three zones of the cortex:

• Zona glomerulosa: aldosterone (mineralocorticoid).
• Zona fasciculata: cortisol (glucocorticoid).
• Zona reticularis: DHEA and androstenedione (androgen precursors).

Because fetal and early neonatal adrenal cortex has low 3-beta-hydroxysteroid dehydrogenase activity, much fetal steroidogenesis is directed towards DHEA and DHEA sulphate; the 21-hydroxylase (P450c21) step is essential in both the aldosterone and the cortisol branches. The adrenal can also synthesise small amounts of testosterone via 17-beta-HSD5 (AKR1C3), and an "11-oxyandrogen" pathway converts androstenedione to 11-beta-hydroxyandrostenedione and then 11-ketotestosterone.^[1]

The central rule: a block creates (1) deficiency of everything downstream, always cortisol and sometimes aldosterone or sex steroids; (2) accumulation and shunting of precursors upstream; and (3) diversion along routes that are ordinarily minor, producing unique biomarkers such as 21-deoxycortisol in 21-OHD. The defects that affect only the adrenal (21-OHD, 11-OHD) differ from those that also affect gonadal steroidogenesis (17-OHD, 3-beta-HSD, P450 oxidoreductase, lipoid CAH).^[2]

In 21-OHD, loss of 21-hydroxylase means progesterone and 17-hydroxyprogesterone (17-OHP) cannot become deoxycorticosterone (DOC) and 11-deoxycortisol, so cortisol (and, in severe disease, aldosterone) falls. The mass of accumulated 17-OHP overflows into androstenedione and testosterone and can also be 11-hydroxylated to 21-deoxycortisol, a specific biomarker. ACTH rises, driving adrenal hyperplasia and further androgen overproduction; in 75 percent of classic cases aldosterone synthesis is also inadequate and produces salt wasting, failure to thrive, and potentially fatal hypovolaemia and shock in the newborn.^[1]

In males, the gonads are the main source of testosterone, so androgen excess in 21-OHD does not deform the male genitalia but causes rapid growth, advanced skeletal maturation and early pubarche after birth. In females, adrenal androgens virilise the external genitalia in utero, producing a 46,XX disorder of sex development ranging from clitoromegaly to a fully masculinised appearance with a phallic urethra and fused labioscrotal folds.^[1]

For completeness, the biochemical signatures are: 17-OHD raises DOC and corticosterone while 17-OHP and androgens are low; 11-OHD raises DOC, 17-OHP, androgens and 11-deoxycortisol with only cortisol low; the classic 21-OHD table entry for elevated steroids is 17-OHP (and 21-deoxycortisol) and for low steroids is cortisol (and aldosterone in severe disease).^[2]

The one combination that should make CAH obvious is ambiguous genitalia in a genetic female plus a medical emergency in a genetic male.

• 46,XX infant: variable virilisation of the external genitalia – an enlarged clitoris, partly or completely fused labioscrotal folds, and a urogenital sinus. The internal structures (ovaries, uterus, fallopian tubes) are normal. Severe forms can be misread as a male with hypospadias and bilateral cryptorchidism, which is why any newborn with "bilateral non-palpable gonads" needs CAH considered.^[1]
• 46,XY infant: the genitalia look normal at birth, so disease is missed until a salt-wasting crisis appears, usually between day 5 and day 14 of life and sometimes as late as a month. Vomiting, poor feeding, lethargy, hypoglycaemia, hyponatraemia, hyperkalaemia and shock follow. A relative lack of salt-wasting males in unscreened case series has been interpreted as death from undiagnosed crisis.^[1]
• 11-OHD: 46,XX infants also have ambiguous genitalia; hypertension may appear early, although newborns are relatively resistant to mineralocorticoids, so hypokalaemia is uncommon initially.
• 17-OHD: infants of both sexes look female (46,XY sex reversal), because no androgens are made; the condition is silent in the newborn.

Classic (salt-wasting and simple virilising) disease, if undiagnosed or undertreated, produces rapid linear growth, advanced bone age, early pubarche and precocious puberty in both sexes; adult stature ends short if treatment is delayed. Acne, accelerated skeletal maturation and Cushingoid change are treatment hazards rather than disease features. Hyperpigmentation reflects high ACTH. In boys, testicular adrenal rest tumours (TARTs) may appear at puberty and beyond.^[1][2]

• Females with 21-OHD: primary amenorrhoea or oligomenorrhoea, hirsutism, acne, anovulatory infertility. Nonclassic disease often first presents with these symptoms and is easily confused with polycystic ovary syndrome.
• Males with 21-OHD: may be diagnosed only after accelerated growth in childhood or as an incidental adrenal mass in adulthood; TARTs and subfertility are the main problems.
• 11-OHD: precocious adrenarche, virilisation, hypertension and (in females) menstrual disturbance.
• 17-OHD: primary amenorrhoea and absent puberty in both 46,XX and 46,XY females; hypertension and hypokalaemia; boys are phenotypically female at birth. Pregnancy has been reported after ovulation induction in 46,XX women; fertility is not established in 46,XY patients.^[2]

• Often asymptomatic and found on screening at any age.
• When symptomatic in childhood: premature pubarche, accelerated growth and bone age.
• In adult women: hirsutism, acne, menstrual irregularity, anovulatory infertility.
• In most adult men: asymptomatic; treatment is usually not needed unless infertility, TARTs, or an intermediate phenotype.^[1][7]

CAH and its treatments place a real burden on patients and families: repeated hospital visits, atypical genital development, fertility worries, chronic medication, and attention to body image. The Endocrine Society guideline recommends behavioural and mental health consultation and evaluation for patients and parents, with a low threshold for referral to psychological or psychiatric care with expertise in CAH-related problems.^[1]

In a newborn, ambiguous genitalia or a salt-wasting crisis needs to be sorted from the other causes of 46,XX virilisation (aromatase deficiency, maternal androgen or virilising tumour exposure, placental aromatase deficiency), 46,XY under-virilisation (androgen insensitivity, 5-alpha-reductase deficiency, testosterone biosynthesis defects), congenital adrenal hypoplasia (NR0B1/DAX-1), and adrenal haemorrhage. In an adult woman, nonclassic CAH must be distinguished from polycystic ovary syndrome, Cushing syndrome, and androgen-secreting tumours. The clues are the 17-OHP level, the blood pressure (high in 11-OHD and 17-OHD), and an electrolyte panel.

All newborn screening programmes should include CAH due to 21-OHD.^[1] The first-tier test measures 17-OHP on a dried blood spot, ideally using an assay standardized to a common technology with norms stratified by gestational age rather than birth weight, because 17-OHP correlates better with gestational age. Premature, sick and stressed infants have higher 17-OHP, which lowers the positive predictive value in that group, and immunoassays can cross-react with other steroids. A second-tier screen by liquid chromatography-tandem mass spectrometry (LC-MS/MS) on the original dried blood improves specificity and positive predictive value; where LC-MS/MS is unavailable, cosyntropin stimulation should be used to confirm the diagnosis before starting glucocorticoids.^[1]

Screening should be timed after the first 24 to 48 hours of life because samples taken immediately after birth give many false positives and false negatives. If a gestational-age-adjusted 17-OHP screen is positive, refer to paediatric endocrinology where available and proceed to confirmatory testing.

Where screening is universal it shortens the time to diagnosis and reduces morbidity and mortality from salt-wasting crisis; unscreened infants have a death rate from salt-wasting that has been reported around 0 to 10 percent depending on setting, and a positive predictive value of screening of roughly 25 percent in term infants but under 2 percent in preterm infants in large series.^[1]

• Venous sodium and potassium, glucose, creatinine, blood gas and plasma renin (or renin activity). Hyponatraemia with hyperkalaemia is the classic salt-wasting pattern; plasma renin is high in salt wasting and suppressed in 11-OHD and 17-OHD because of DOC-mediated volume expansion.
• Morning (before 08:00) serum 17-OHP by LC-MS/MS: under 2 ng/mL by immunoassay is generally considered normal in older patients, while above 7 to 10 ng/mL is considered diagnostic of CAH; for LC-MS/MS, above 0.8 ng/mL is elevated and values above 3 ng/mL after cosyntropin stimulation confirm the diagnosis. Values between about 2 and 7 ng/mL are indeterminate and need stimulation testing.^[4]
• Where the baseline 17-OHP is clearly raised in symptomatic patients, proceed to confirmatory testing. A baseline value in the low range for the assay and time of day makes 21-OHD very unlikely.^[5][6]
• Extended steroid profile: cortisol, 11-deoxycorticosterone, 11-deoxycortisol, 17-hydroxypregnenolone, dehydroepiandrosterone and androstenedione by LC-MS/MS. Adding 21-deoxycortisol improves the diagnostic hit rate because it is highly specific for 21-OHD. This panel distinguishes 21-OHD from 11-OHD, 3-beta-HSD deficiency and P450 oxidoreductase deficiency.^[1][4]
• Other steroids are often raised in 21-OHD: 21-deoxycortisol, androstenedione, testosterone (females) and, in severe classic disease, renin and aldosterone patterns as above.

A cosyntropin stimulation test should not be performed in the first 24 to 48 hours of life; at birth false positives and negatives are common.^[1]

If the morning 17-OHP is borderline, give cosyntropin (synthetic ACTH 1-24) in standard dose: 0.25 mg intravenously or intramuscularly (0.125 mg in infants with very low birth weight), and sample baseline and 60 minutes later for 17-OHP, cortisol and, where available, the rest of the profile. Collecting a 30-minute sample as well is reasonable when adrenal reserve is also being assessed.^[1][8]

Interpretation: a stimulated 17-OHP above 10 ng/mL (above 30.3 nmol/L) supports 21-OHD; in practice classic disease usually exceeds 100 ng/mL (above 302.6 nmol/L), whereas nonclassic disease falls between 10 and 100 ng/mL (30.3 to 302.6 nmol/L), or 1,500 to 10,000 ng/dL in older literature. A 17-OHP above 1,000 ng/dL after stimulation is commonly taken to confirm 21-OHD, and above 1,500 ng/dL makes the diagnosis definitive; classic CAH typically reaches above 20,000 ng/dL. Cortisol is measured to document adrenal reserve; stimulated 17-OHP is not specific and can be raised in 11-OHD, 3-beta-HSD deficiency and P450 oxidoreductase deficiency, so the result must be read with the blood pressure, electrolytes and the full panel.^[5][6][8]

Genotyping is suggested when the cosyntropin profile is equivocal, when stimulation cannot be done accurately (because the patient is already taking glucocorticoids), or for genetic counselling. Because CYP21A2 lies in a region with a highly homologous pseudogene, duplications, deletions and rearrangements make genotyping error-prone; testing at least one parent helps to phase mutations. About 300 CYP21A2 mutations are known. For the uncommon forms, CYP11B1 and CYP17A1 mutations account for 11-OHD and 17-OHD.^[1][2]

Bone age (radiograph of the left wrist) is assessed annually from early childhood until near-adult height; in children under 2 years it is advised yearly. Imaging of the adrenal glands is not routine in adults with classic disease; reserve it for suspected adrenal mass, poor control, a lapse in treatment of several years, or failure to respond to intensified therapy. Males with classic 21-OHD need periodic testicular ultrasound for adrenal rest tumours. Pelvic ultrasonography in adolescent females checks functional female anatomy without vaginal stenosis.^[1]

Treat as for adrenal insufficiency in any age: airway, breathing and circulation; intravenous 0.9% saline with dextrose; glucocorticoid as an intravenous bolus (hydrocortisone) and then infusion; correct hyperkalaemia and hypoglycaemia; monitor electrolytes and blood pressure closely. Infants need frequent weighing and at least daily, sometimes every second day, biochemical monitoring in the first weeks. Stress-dose coverage applies to any serious intercurrent illness (see below). Hyperpigmentation from ACTH excess usually fades after treatment.

Hydrocortisone is the recommended glucocorticoid for growing patients with classic 21-OHD; long-acting potent glucocorticoids and oral hydrocortisone suspensions should be avoided in growing children because of growth suppression and uneven liquid distribution. Typical maintenance dosing is 10 to 15 mg/m2 per day in three divided doses; younger infants are often started higher (around 20 to 30 mg/m2 per day) and then reduced. Adults may use daily hydrocortisone and/or longer-acting glucocorticoids, plus mineralocorticoids as clinically indicated. Hydrocortisone is given with food and the largest dose taken in the early morning; some patients need a late-evening dose to suppress the nocturnal ACTH rise.^[1][3][10]

Dose individualisation aims to suppress androgen excess enough to normalise growth and puberty while avoiding overtreatment, which causes weight gain, hypertension and poor growth. Monitoring combines growth velocity, weight, blood pressure, physical examination and timed biochemical measurements (renin, testosterone, androstenedione, 17-OHP) in relation to the medication schedule. Infants are reviewed very closely in the first 3 months and then every 3 months until 18 months; after that every 4 months; adults annually. Complete suppression of endogenous adrenal secretion should be avoided in adults because of the harm of over-treatment.^[1]

All classic 21-OHD infants need fludrocortisone (9-alpha-fludrocortisone) and sodium chloride supplements from early life, even some simple virilising patients, because subclinical mineralocorticoid deficiency is present in all 21-OHD. Mineralocorticoid requirement is higher in infancy (0.05 to 0.2 mg/day, sometimes expressed as about 150 micrograms/m2/day) and falls as the child grows; fludrocortisone doses above this range risk hypertension, oedema and hypokalaemia. Sodium supplements of 1 to 2 g/day (about 17 to 34 mEq/day) or 1 to 3 g/day in some low-resource regimens are given in several feeds in infancy and can be stopped as the diet becomes salty. Serum electrolytes, blood pressure and plasma renin activity guide titration. Mineralocorticoid is usually unnecessary in 11-OHD and 17-OHD, where DOC produces mineralocorticoid excess.^{[1][2][8][10]}

Fever above 38.5 degrees Celsius, gastroenteritis with dehydration, major surgery with general anaesthesia and major trauma all require an increased glucocorticoid dose; everyday emotional stress, minor illness and routine exercise do not. Patients and carers should be taught to double or triple the oral hydrocortisone dose (commonly 30 to 50 mg/m2 per day in 3 to 4 divided doses during illness, roughly three times the maintenance dose) for moderate illness, with one practice guideline suggesting 50 to 75 mg/m2 per day (three to five times the daily dose) for stress. Parenteral stress doses vary by guideline and age: one source gives about 25 mg intramuscularly in infancy rising to 50 mg in childhood, and adolescents and adults receive larger doses, so follow the local emergency protocol; ongoing coverage is then given as a multiple of the maintenance dose intravenously in divided doses. For major surgery, 50 to 100 mg/m2 intravenously before induction then repeated doses for 24 to 48 hours are used in severe stress protocols. Every patient should carry medical identification and an emergency glucocorticoid injection kit, with carers trained in parenteral administration. Stress dosing increases glucocorticoid, not mineralocorticoid.^[1][9][10]

These figures are commonly used rather than evidence-settled: paediatric practice varies by centre, so follow the local adrenal insufficiency protocol and check the current product information. Mineralocorticoid stress coverage is not needed.

Surgery. Genital surgery in virilised girls (clitoroplasty and urogenital sinus repair) is now framed as shared decision-making. The Endocrine Society's systematic review could not identify enough rigorous studies to define a favourable benefit-to-risk ratio for either early or late elective genital reconstructive surgery. Parents (and older children) are informed of all options including observation and delay; surgery should be performed only in centres with experienced paediatric surgeons/urologists, paediatric endocrinologists, paediatric anaesthetists, mental health professionals and social work, after extensive counselling and fully informed consent. Severe clitoromegaly may warrant neurovascular-sparing clitoroplasty when surgery is chosen. Surgery does not replace glucocorticoid therapy; it does not correct the hormonal disorder. Vaginal dilatation and lubricants are needed later, and obstetric care is affected by anatomy; caesarean section is often used.^[1]

Psychosocial care. As above: behavioural and mental health consultation for patients and parents, support groups, and honest age-appropriate discussion of the diagnosis, fertility and sexual function.

Transition to adult care. Transition should start several years before leaving paediatric endocrinology, ideally through joint clinics of paediatric endocrinology, reproductive endocrinology, adult endocrinology and urology. Adolescent females need gynaecological assessment for functional anatomy and menstrual regularity.^[1]

Women with nonclassic disease who are infertile or have recurrent miscarriage should be treated with a glucocorticoid that does not cross the placenta (such as hydrocortisone), stopping dexamethasone and other placenta-crossing glucocorticoids once pregnancy is planned or confirmed. In pregnant women with classic CAH, continue pre-pregnancy doses of hydrocortisone or prednisolone and fludrocortisone, with increases in the second or third trimester if needed and stress doses in labour and delivery; avoid dexamethasone in pregnancy because it crosses the placenta. Endocrine (CAH-familiar) and obstetric specialists should co-manage pregnancy and birth. Women with nonclassic CAH do not need glucocorticoid in pregnancy unless there are infertility, virilisation or miscarriage indications. Men with TARTs or fertility impairment need endocrine review; glucocorticoids may help fertility by suppressing ACTH-driven adrenal androgens.^[1][7]

Adults with classic CAH are at increased risk of obesity, hypertension, insulin resistance and low bone density, particularly after periods of relatively high glucocorticoid dosing; they should have lifestyle advice from early childhood to keep body mass index normal, bone mineral density screening after prolonged high-dose steroid exposure or fragility fracture, and annual physical examinations including blood pressure, BMI and Cushingoid features with timed hormone measurements. Routine adrenal imaging is not recommended. Cardiac and metabolic disease should be monitored as for the general population.^[1]

• Adrenal crisis in classic disease if treatment is interrupted or stress cover omitted.
• Short stature from late diagnosis or over-treatment.
• Hypertension and hypokalaemia in 11-OHD and 17-OHD.
• TARTs and ovarian adrenal rest tumours, causing infertility.
• Altered genital anatomy, sexual dysfunction, continence problems after surgery or from severe virilisation.
• Psychological morbidity, including anxiety and depression, correlated with chronic illness burden.
• Accumulated cardiovascular and metabolic risk from both disease and its treatment.
• Loss of bone density after prolonged high-dose glucocorticoid.

With newborn screening, adequate replacement and psychosocial support, survival is excellent and most patients reach normal adult height and fertility. Unscreened salt-wasting disease carries substantial infant mortality. Nonclassic disease has an excellent prognosis and many patients never need daily treatment. Long-term data on cognition and metabolism in prenatally treated fetuses remain conflicting.

Prevention is genetic. Carrier testing and prenatal counselling are offered to parents of an affected child and to known carriers. Carriers of classic 21-OHD are common in the general population. Newborn screening is the population-level prevention of deaths and missed diagnoses; LC-MS/MS second-tier testing is the best way to keep the positive predictive value acceptable. Screening itself does not diagnose or treat; it triggers confirmatory testing and treatment.^[1]

Prenatal diagnosis is offered when both parents are known carriers or have had an affected child. The aim is to identify affected females before the critical window of genital development so that virilisation can be prevented.

• Risk: a previously affected couple has a 1 in 4 chance of an affected fetus and a 1 in 8 chance of an affected female.
• Because genital differentiation begins very early in the first trimester, any empirical treatment must start before then, before chromosomal sex and genotype are known.
• Prenatal testing options: SRY or sex-determining region Y DNA in maternal blood (early first trimester), chorionic villus sampling later in the first trimester, and amniocentesis in the second trimester, with CYP21A2 genotyping.
• Dexamethasone crosses the placenta (cortisol and prednisolone do not, being inactivated by placental 11-beta-HSD2) and is used in virtually all reported prenatal regimens at about 20 micrograms/kg of prepregnancy maternal body weight per day, up to about 1.5 mg/day, in divided doses; treatment is continued to term only if the fetus is an affected female, and otherwise stopped when non-affected or male sex is confirmed. Reduced doses have been proposed.^[1]

The Endocrine Society advises that prenatal therapy be regarded as experimental; it should be provided only through institutional review board-approved protocols at centres able to collect outcomes on enough patients for the risks and benefits to be defined, with Y-chromosomal DNA screening in maternal blood to exclude male fetuses. Research protocols should include long-term follow-up registries. The potential benefits must be weighed against uncertain but reported risks to cognition, metabolism and maternal health, and against performing reconstructive surgery after birth instead. Counselling must be non-directive and should acknowledge the controversy.^[1]

Children. Classic CAH is diagnosed in infancy and treated from the neonatal period. Growth and puberty are the main barometers of treatment quality. Bone age is checked annually. Stress-cover planning, school and sports arrangements, and age-appropriate self-management all matter. Daily hydrocortisone and fludrocortisone should be adjusted for intercurrent illness.

Adolescents. A nonjudgemental discussion of adherence, body image, sexual health and fertility should be routine, with a structured transition plan.

Adults. Monitoring, contraception and fertility, blood pressure and bone density move to the foreground.

Pregnancy. Co-management by an endocrinologist familiar with CAH and an obstetric specialist; avoid glucocorticoids that cross the placenta; stress doses in labour and delivery.^[1]

Older adults. Long-term cumulative glucocorticoid exposure complicates cortisol replacement; check bone density, blood pressure and metabolic markers. The evidence for cardiovascular and metabolic morbidity in CAH is observational and of low certainty; routine screening beyond that recommended for the general population is not advised, but clinicians should use judgement.^[1]

• Newborn screening may not exist; teach recognition of virilised female newborns and of salt-wasting in newborn males, which is usually fatal if missed. Screening timing from 24-48 hours and early empiric treatment save lives.
• Laboratory support is often limited: a single morning 17-OHP (or even clinical diagnosis) must suffice; a simple electrolyte panel and a manual blood pressure already distinguish salt-wasting from mineralocorticoid-excess forms.
• LC-MS/MS, cosyntropin stimulation, genetic testing and paediatric endocrinology are frequently unavailable; empirical treatment based on phenotype (virilisation, blood pressure) is then justified, with referral where possible.
• Hydrocortisone and fludrocortisone in small-dose formulations may be unavailable; hydrocortisone tablets can be crushed, but the cypionate suspension is not recommended for CAH because of bioinequivalence. Compounded suspensions need care. Fludrocortisone 0.05 to 0.2 mg/day is required in all classic disease. Sodium supplements of 1 to 3 g/day should be given in several feeds to salt-wasting infants.
• Stress dosing can be taught with weight-based household measures; every family should have a written emergency card and, where possible, an injectable hydrocortisone kit (100 mg vials) with carer training. Gastroenteritis is the commonest trigger of crisis.
• Surgery for virilised girls, mental health support and genetic counselling are often centralised; families should be referred early and long-term follow-up maintained.^[1][9][10]

• adrenal insufficiency and adrenal crisis
• disorders of sex development
• delayed puberty and primary amenorrhoea
• hirsutism and hyperandrogenism
• fertility and ovulation induction
• paediatric endocrinology and growth monitoring

• CAH is a group of autosomal recessive enzyme defects in adrenal steroidogenesis; 21-hydroxylase deficiency accounts for about 95 percent and is the prototype.
• Classic 21-OHD occurs in roughly 1 in 14,000 to 1 in 18,000 births; nonclassic disease is much commoner, near 1 in 200 overall.
• The pathophysiology is always cortisol deficiency plus shunting of precursors into androgen synthesis; aldosterone may also be deficient or in excess depending on the enzyme.
• Classic 21-OHD presents as ambiguous genitalia in 46,XX newborns and as a salt-wasting crisis in 46,XY newborns; nonclassic disease presents with premature adrenarche, hirsutism, anovulation and infertility.
• 11-OHD and 17-OHD both produce hypertension because deoxycorticosterone acts as a mineralocorticoid; 17-OHD additionally abolishes sex steroid synthesis.
• Diagnosis rests on newborn 17-OHP screening, early-morning 17-OHP by LC-MS/MS and cosyntropin stimulation (standard dose 0.25 mg; roughly 0.125 mg in very low birth weight); stimulated 17-OHP above 10 ng/mL supports and above 1,500 ng/dL is diagnostic of 21-OHD.
• Treatment is hydrocortisone 10 to 15 mg/m2 per day in three divided doses for growing patients, plus fludrocortisone 0.05 to 0.2 mg/day and sodium supplements in classic disease.
• Stress doses are needed for fever above 38.5 degrees Celsius, dehydrating gastroenteritis, major surgery and trauma, but not for everyday stress; oral stress dosing is commonly 30 to 50 mg/m2 per day.
• Genital surgery is a shared decision in specialised centres; psychosocial care and transition planning are core, not optional.
• Prenatal dexamethasone is experimental, should be IRB-approved, uses about 20 micrograms/kg per day up to 1.5 mg/day, and excludes male fetuses from treatment.
• Low-resource care depends on clinical recognition, cheap electrolyte panels, generic hydrocortisone and fludrocortisone, family emergency education and early referral.