Congenital Adrenal Hyperplasia

• Primary enzymatic defect and cortisol synthesis failure: In 21-hydroxylase deficiency (the most common form, CYP21A2 gene mutation), the enzyme 21-hydroxylase cannot convert both 17-hydroxyprogesterone (17-OHP) to 11-deoxycortisol in the cortisol synthesis pathway and progesterone to deoxycorticosterone (DOC) in the mineralocorticoid pathway. This results in profound deficiency of both cortisol and aldosterone. The hypothalamic-pituitary-adrenal (HPA) axis responds to low cortisol levels by increasing ACTH secretion in an attempt to restore cortisol levels, but because the enzymatic defect cannot be overcome, ACTH levels rise dramatically (often 10-100 times normal). This persistent ACTH stimulation causes adrenal hyperplasia—compensatory proliferation of adrenocortical tissue—which is the hallmark histologic finding and gives the disorder its name. Neonates with salt-wasting CAH may present as early as 1-4 weeks of life with hyponatremia, hyperkalemia, metabolic acidosis, and hypovolemic shock due to severe mineralocorticoid deficiency.

• Shunting of steroid precursors into alternative pathways and androgen excess: With the enzymatic block at 21-hydroxylase, the accumulated precursor 17-OHP cannot proceed through the normal cortisol synthesis pathway and instead is shunted into the 17,20-lyase pathway (via 17,20-lyase activity of CYP17A1), producing large quantities of 17-hydroxypregnenolone and downstream androgens including androstenediol, testosterone, and androstenedione. In girls, this excess androgen production leads to virilization in utero, beginning at approximately 8 weeks of gestation when fetal adrenal androgen production becomes sufficient to suppress müllerian structures and virilize external genitalia. The degree of virilization at birth (classified by Tanner staging or the Prader scale) depends on the timing and magnitude of androgen exposure during gestation. In boys, the excess androgens cause accelerated linear growth, advanced bone age, and precocious puberty, though the diagnosis may be initially missed because genital development appears "normal" and is thus not flagged as abnormal at birth.

• Severity classification based on degree of enzymatic impairment: The classic salt-wasting (SW) form (approximately 75% of classic CAH cases) results from severe deficiency of both enzymes (cortisol and mineralocorticoid pathways completely blocked), presenting with cortisol, aldosterone, and androgen abnormalities. The simple virilizing (SV) form (approximately 25% of classic CAH) results from less severe 21-hydroxylase deficiency, with some residual enzyme activity sufficient to maintain minimally adequate aldosterone synthesis but still producing severe androgen excess and cortisol deficiency; these patients manifest virilization but typically retain normal serum sodium and do not develop classic salt-wasting crises. The non-classic form, caused by mutations that allow substantial residual enzymatic activity, presents later in life (adolescence to early adulthood) with mild hyperandrogenism and normal cortisol and aldosterone levels; many cases are detected only during workup for hirsutism or infertility rather than in the neonatal period.

• Additional enzymatic defects and their consequences: While 21-hydroxylase deficiency predominates, other enzymatic defects occur less commonly. 11β-hydroxylase deficiency (the second most common form, ~5-8% of CAH) blocks conversion of 11-deoxycortisol to cortisol and also prevents synthesis of normal mineralocorticoids, but because 11-deoxycortisol accumulation allows some mineralocorticoid activity through DOC accumulation (a weak mineralocorticoid), these patients typically present with hypertension rather than salt wasting—a critical distinguishing feature from 21-hydroxylase deficiency. 3β-hydroxysteroid dehydrogenase deficiency causes accumulation of pregnenolone and 17-hydroxypregnenolone with shunting to the delta-5 pathway producing dehydroepiandrosterone (DHEA) excess; this form may cause hyponatremia and hyperkalemia (like salt-wasting disease) but also may cause insufficient virilization in genetic males because early fetal development relies partly on testosterone production. 17α-hydroxylase deficiency prevents synthesis of both cortisol and sex steroids, resulting in cortisol deficiency without androgen excess—these patients present with hypokalemia, hypertension, and primary amenorrhea in 46,XX individuals (due to absent sex steroid production) rather than virilization.

• CYP21A2 gene mutations (21-hydroxylase deficiency): Accounting for 90-95% of all CAH cases, this autosomal recessive condition results from mutations in the CYP21A2 gene located on chromosome 6 in the human leukocyte antigen (HLA) class III region. Over 1,000 different mutations have been identified, including point mutations, deletions, and unequal crossovers with the adjacent pseudogene CYP21A1P. The type of mutation correlates somewhat with phenotype: severe deletions and frameshift mutations typically cause salt-wasting disease, while missense mutations (especially those affecting substrate binding) cause simple virilizing or non-classic disease. This genetic variability underlies the clinical heterogeneity observed even within families, though most families segregate a consistent phenotype based on their specific mutations.

• CYP11B1 gene mutations (11β-hydroxylase deficiency): The second most common form of CAH, representing 5-8% of cases, results from mutations in the CYP11B1 gene on chromosome 8. These mutations impair the enzyme 11β-hydroxylase, which catalyzes the final step in both cortisol and corticosterone synthesis. A critical distinguishing feature of 11β-hydroxylase deficiency is that accumulation of 11-deoxycortisol (and especially 11-deoxycorticosterone, DOC) provides substantial mineralocorticoid activity, preventing salt wasting and instead producing hypertension, hypokalemia, and metabolic alkalosis—a distinctly different presentation from 21-hydroxylase deficiency that can lead to diagnostic confusion if not carefully considered.

• CYP17A1 gene mutations (17α-hydroxylase deficiency): A rare form of CAH, this mutation impairs both cortisol and sex steroid synthesis, presenting with cortisol deficiency without androgen excess, resulting in primary hypogonadism and absence of secondary sexual characteristics in addition to glucocorticoid insufficiency. Patients typically present in late adolescence with primary amenorrhea (46,XX individuals) or sexual infantilism (46,XY individuals), though cortisol insufficiency may be clinically silent if baseline cortisol production is minimally adequate.

• HSD3B gene mutations (3β-hydroxysteroid dehydrogenase deficiency): The least common form of CAH, HSD3B1 mutations cause deficiency of 3β-hydroxysteroid dehydrogenase, which is essential for conversion of pregnenolone to progesterone and DHEA to androstenedione in all steroid synthesis pathways. Classic 3β-HSD deficiency can present with salt wasting (due to mineralocorticoid deficiency) but may paradoxically cause undervirilization in genetic males because the initial surge of fetal testosterone production depends on delta-5 pathway steroids (particularly androstenediol and DHEA) rather than delta-4 pathway products.

• Ethnic and population-specific risk factors: CAH demonstrates marked geographic and ethnic variation, with highest incidence in populations of Ashkenazi Jewish descent (1:280), Hispanic populations (1:340-590), Saudi Arabian populations (1:2,200), and Native American populations, while incidence is lower in Northern European and African populations (1:15,000-18,000). This variation reflects founder effects and different mutation frequencies in isolated populations. Consanguinity increases risk in populations where carrier frequency is high.

• Neonatal salt-wasting crisis (classic salt-wasting CAH, typical onset 1-4 weeks of life): The most severe and acute presentation occurs in neonates with classic 21-hydroxylase deficiency and complete mineralocorticoid deficiency. These infants initially appear well at birth but present between 1-4 weeks of age with progressive symptoms of adrenal crisis: poor feeding, lethargy, vomiting, progressive weight loss despite adequate caloric intake, and rapid deterioration into hypovolemic shock. Laboratory findings reveal hyponatremia (typically 120-130 mEq/L), hyperkalemia (often >6 mEq/L with peaked T waves on electrocardiogram), and metabolic acidosis. The physiologic basis is severe aldosterone deficiency, preventing sodium reabsorption in the collecting duct, resulting in urinary sodium wasting, hypovolemia, and prerenal azotemia with elevated blood urea nitrogen and creatinine. This presentation is now less common in regions with newborn screening because the diagnosis is often established before symptoms develop, but it remains the leading cause of death in unrecognized CAH and may still occur in regions without screening or in missed cases.

• Classic simple virilizing CAH in 46,XX individuals (typically recognized at birth or in early childhood): Female infants born with classic simple virilizing CAH manifest virilization of external genitalia due to in utero androgen exposure from 8 weeks of gestation onward. The degree of virilization is classified using the Prader scale (stage 1: mild clitoromegaly only; stage 2-3: partial virilization with clitoromegaly and partial labial fusion; stage 4-5: complete virilization mimicking male external genitalia with complete labial fusion and urogenital sinus). This is typically noted immediately at birth and prompts investigation, though in cases of mild virilization it may be attributed to prematurity or maternal androgen exposure. Importantly, 46,XX infants with CAH have normal internal reproductive structures (uterus, fallopian tubes, ovaries) because müllerian structures form independently of androgen exposure and are only suppressed by anti-müllerian hormone (AMH) from fetal Sertoli cells, which these individuals lack. Beyond the neonatal period, virilized girls demonstrate accelerated linear growth, advanced bone age, male-pattern hair growth (including pubic hair in early infancy), facial acne, and lack of breast development or menses at expected puberty if untreated—essentially developing male-typical pubertal characteristics while retaining female reproductive organs.

• Simple virilizing CAH in 46,XY individuals (often diagnosed late or missed initially): Genetic males with simple virilizing CAH may not be recognized at birth because their external genitalia appear phenotypically male due to testosterone excess, though may be slightly enlarged. These boys typically present in early childhood (ages 1-5 years) with precocious puberty manifestations: rapid linear growth (often standing above 95th percentile for age), muscular development inappropriate for age, pubic and axillary hair development, genital enlargement with increased penile length but not testicular enlargement (distinguishing gonadotropin-independent precocious puberty from true central precocious puberty, which would present with testicular enlargement), and acne. The bone age advances rapidly, and without treatment, premature epiphyseal fusion occurs, ultimately resulting in short adult stature despite early tall stature in childhood. The diagnosis is often suspected when growth acceleration and virilization are disproportionate to testicular development or when precocious puberty is documented in an infant or very young child.

• Non-classic CAH (typically presenting in adolescence or adulthood): Non-classic CAH, caused by mutations allowing substantial residual enzyme activity, presents much later and more insidiously. Affected individuals often have mild to moderate hyperandrogenism without the severe virilization or salt wasting of classic disease. 46,XX individuals typically present with hirsutism (male-pattern hair growth on face, chest, and abdomen), acne, or oligomenorrhea/infertility in adolescence or early adulthood, often being mistaken for polycystic ovary syndrome (PCOS). Some patients are asymptomatic and discovered incidentally during testing for other reasons or as family members of affected individuals. 46,XY individuals with non-classic disease are rarely identified because mild androgen excess is clinically silent, though they may occasionally present with infertility or cryptorchidism.

• Classic salt-wasting CAH in 46,XY individuals (recognized due to salt-wasting crisis rather than virilization): While 46,XX individuals with salt-wasting CAH are typically recognized at birth due to virilization, 46,XY individuals with salt-wasting disease may initially escape detection at birth because their genitalia appear phenotypically normal. These boys may present with the life-threatening salt-wasting crisis described above at 1-4 weeks of age without preceding virilization findings that would have alerted clinicians to the diagnosis.

• 11β-hydroxylase deficiency (hypertension and hypokalemia, not salt wasting): In contrast to 21-hydroxylase deficiency, patients with 11β-hydroxylase deficiency present with hypertension, hypokalemia, and metabolic alkalosis secondary to mineralocorticoid excess (DOC accumulation) rather than mineralocorticoid deficiency. They manifest androgen excess causing virilization (in females) and precocious puberty (in males), but without the salt-wasting component, making this an important differential consideration when a CAH-like presentation includes hypertension as a prominent feature.

• 17α-hydroxylase deficiency (primary hypogonadism, hypertension, hypokalemia): Patients present with primary hypogonadism and sexual infantilism due to absent sex steroid production, combined with hypertension and hypokalemia from mineralocorticoid excess. 46,XX individuals present with primary amenorrhea, complete absence of breast development, and lack of axillary/pubic hair development. 46,XY individuals present with micropenis, undescended testes, and lack of male sexual development.

• 3β-hydroxysteroid dehydrogenase deficiency (mixed presentation with salt wasting ± undervirilization in males): May present with salt-wasting crisis similar to 21-hydroxylase deficiency due to mineralocorticoid deficiency, but is distinguished by accumulation of DHEA and androstenediol. Genetic males may paradoxically show undervirilization or ambiguous genitalia at birth because early fetal virilization depends on delta-5 pathway androgens that are blocked in this condition.

• Newborn screening (first-line detection in United States and many developed countries): Most U.S. states and many developed countries now screen for 21-hydroxylase deficiency CAH using dried blood spot testing measuring 17-hydroxyprogesterone (17-OHP) from heel-stick samples collected at 24-48 hours of life. The typical cutoff is >4 ng/mL or >12 nmol/L, with sensitivity approaching 95-99% for classic disease but lower (~80%) for non-

Immediate stabilisation (salt-wasting crisis is a medical emergency)

• Volume resuscitation: isotonic saline bolus (20 mL/kg) for hypovolemic shock, with dextrose-containing fluid because cortisol deficiency causes hypoglycemia via impaired gluconeogenesis.
• Parenteral glucocorticoid: hydrocortisone IV/IM given immediately after drawing a confirmatory sample — do not delay treatment for laboratory results. Hydrocortisone is chosen over dexamethasone in crisis because at stress doses it also provides mineralocorticoid receptor activity.
• Hyperkalemia management: ECG first; calcium gluconate for membrane stabilisation if ECG changes, then insulin/dextrose. Fludrocortisone is not useful acutely because volume and hydrocortisone correct the deficit faster.

Maintenance therapy (Endocrine Society Clinical Practice Guideline on CAH due to 21-hydroxylase deficiency)

• Glucocorticoid: hydrocortisone, divided doses, is first-line in growing children — its short half-life minimises growth suppression. The aim is to replace cortisol and suppress ACTH-driven adrenal androgen output, not to normalise 17-OHP completely (normalisation implies overtreatment).
• Mineralocorticoid: fludrocortisone for all classic salt-wasting patients, plus sodium chloride supplementation in infants, whose milk-based diet is sodium-poor.
• Longer-acting glucocorticoids (prednisolone, dexamethasone) are options only after epiphyseal fusion in adults.
• Stress dosing: two- to three-fold increase during febrile illness, vomiting, trauma, or surgery, with an emergency injectable hydrocortisone kit and medical alert identification.

Emergencies

• Acute adrenal crisis: the leading cause of death in CAH. Cortisol deficiency removes the permissive effect on catecholamine-mediated vasoconstriction while aldosterone deficiency depletes intravascular volume. Signalled by vomiting, hypotension unresponsive to fluids alone, hypoglycemia, hyponatremia, and hyperkalemia — typically precipitated by intercurrent illness or missed stress dosing.
• Hyperkalemic arrhythmia: aldosterone deficiency impairs collecting-duct potassium secretion. Peaked T waves progressing to QRS widening and sine wave demand immediate calcium and potassium-lowering therapy.

Complications of the disease itself

• Compromised adult height: adrenal androgens aromatise to estrogen and accelerate epiphyseal maturation; the child is tall early but fuses prematurely. Signalled by bone age advanced beyond chronological age.
• Secondary central precocious puberty: chronic androgen priming of the hypothalamus can trigger true GnRH-dependent puberty once glucocorticoid therapy is started; signalled by testicular enlargement or pubertal LH on GnRH testing, treated with a GnRH agonist.
• Testicular adrenal rest tumors (TART): ACTH-stimulated ectopic adrenal tissue in the rete testis causes obstructive azoospermia and infertility. Bilateral, non-tender testicular masses on scrotal ultrasound in a poorly controlled male — the classic tested association.
• Female subfertility and anovulation: androgen and progesterone excess disrupt the LH surge and endometrial receptivity, mimicking PCOS.

Complications of treatment

• Iatrogenic Cushing syndrome / glucocorticoid overtreatment: growth deceleration crossing percentiles, central obesity, striae, hyperglycemia, reduced bone mineral density.
• Mineralocorticoid overreplacement: hypertension, hypokalemia, and suppressed plasma renin activity — renin is the monitoring parameter.
• Undertreatment: persistent hyperandrogenism with hirsutism, acne, and continued bone-age advance.
• Genitoplasty complications: vaginal stenosis, altered genital sensation, and need for revision surgery in adolescence.

• Elevated 17-hydroxyprogesterone is the fingerprint of 21-hydroxylase deficiency. Markedly elevated on newborn dried blood spot; confirm with a repeat measurement or cosyntropin (ACTH) stimulation test measuring 17-OHP. Prematurity and neonatal stress cause false positives.
• Blood pressure separates the enzyme blocks. Hypotension + hyponatremia + hyperkalemia = 21-hydroxylase. Hypertension + hypokalemia = 11β-hydroxylase (with virilization) or 17α-hydroxylase (without virilization, plus sexual infantilism). The one-line rule: DOC accumulation means hypertension.
• Single best next step in a 2-week-old with vomiting, shock, and hyperkalemia: IV isotonic saline with dextrose plus IV hydrocortisone. Draw the confirmatory 17-OHP first, but never withhold steroid pending the result.
• CAH is the most common cause of ambiguous genitalia in a 46,XX newborn. Internal müllerian structures are normal because there is no AMH — the uterus and ovaries are present. Distractor to avoid: 5α-reductase deficiency and complete androgen insensitivity are 46,XY disorders with absent or undervirilised male anatomy, not virilised females.
• Non-classic CAH masquerades as PCOS. Hirsutism, acne, oligomenorrhea in a teenager or young woman — check an early-morning follicular-phase 17-OHP. Ashkenazi Jewish, Hispanic, and Native American ancestry raise pretest probability.
• Tall child, short adult. Androgens accelerate bone age; without treatment the epiphyses fuse early. Advanced bone age with penile enlargement but prepubertal-sized testes means peripheral (gonadotropin-independent) precocity — not central precocious puberty.
• Monitoring pearl: titrate to androstenedione, growth velocity, bone age, and plasma renin — a fully normal 17-OHP usually means overtreatment.
• Do not give dexamethasone to a growing child, and do not give fludrocortisone in 11β-hydroxylase deficiency.