Congenital adrenal hyperplasia

What it is

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive genetic conditions affecting approximately 1 in 10,000 to 15,000 births worldwide, making it one of the most common causes of differences in sex development (DSD). Also called CAH, it is defined by inherited enzyme deficiencies that block the adrenal glands from synthesizing cortisol normally, triggering a compensatory surge in adrenocorticotropic hormone (ACTH) that enlarges the glands — the "hyperplasia" in the name — and floods the body with androgens. Over 90% of cases stem from a deficiency of the enzyme 21-hydroxylase, encoded by the CYP21A2 gene. CAH spans a wide severity spectrum, from classic CAH — which is apparent at birth and can be life-threatening — to non-classic CAH, which may not surface until adolescence or adulthood and is frequently mistaken for polycystic ovary syndrome (PCOS).

In Canada, newborn screening for CAH is included in provincial heel-prick programs across all provinces and territories, measuring 17-hydroxyprogesterone (17-OHP) to catch classic cases before a salt-wasting crisis develops. Canadian patients are typically managed by pediatric or adult endocrinologists, with glucocorticoid medications such as hydrocortisone available through provincial drug benefit programs.

Causes and mechanism

CAH is inherited in an autosomal recessive pattern: a child must inherit one defective gene copy from each parent to develop the condition. Carriers (one defective copy) are unaffected. If both parents carry the gene, each pregnancy carries a 25% chance of CAH.

The enzyme defect determines the clinical picture. When 21-hydroxylase is absent or severely reduced, the adrenal glands cannot convert precursor molecules into cortisol or aldosterone. Instead, those precursors are shunted into androgen synthesis. The resulting androgen excess begins in utero, which is why female fetuses can be virilized before birth.

Form	Enzyme deficiency	Aldosterone affected?	Key feature
Classic — salt-wasting	21-hydroxylase (severe)	Yes	Life-threatening sodium loss in newborns
Classic — simple virilizing	21-hydroxylase (partial)	No	Androgen excess; no salt crisis
Non-classic (late-onset)	21-hydroxylase (mild)	No	Symptoms in childhood–adulthood; ~1 in 1,000 in some ethnic groups
11-beta hydroxylase deficiency	11β-hydroxylase	No	Second most common; associated with hypertension
Other rare forms	3β-HSD, 17α-hydroxylase, lipoid CAH	Variable	Uncommon; specialist referral required

Symptoms and diagnosis

Symptoms depend heavily on which form is present.

Classic CAH is usually identified at birth or within the first weeks of life:

• Female newborns may have ambiguous genitalia due to prenatal androgen exposure, while internal reproductive organs remain normal
• Salt-wasting crisis — vomiting, dehydration, dangerously low sodium, cardiovascular instability — can occur within the first two weeks and is a medical emergency
• Rapid early childhood growth followed by premature closure of growth plates, often resulting in shorter adult height

Non-classic CAH presents later and more subtly:

• Premature pubic or underarm hair in children (before age 8 in girls, age 9 in boys)
• Severe acne, rapid growth, or early puberty signs in school-age children
• Irregular or absent menstrual periods, hirsutism, or male-pattern hair thinning in women
• Fertility difficulties in adults of any sex
• In adult males, benign testicular adrenal rest tumours (TARTs) can develop and impair fertility

Diagnosis involves:

1. Newborn screening — heel-prick 17-OHP measurement, standard across Canadian provinces
2. Confirmatory blood tests — 17-OHP, cortisol, ACTH, androgens (testosterone, DHEA-S), sodium, potassium
3. ACTH stimulation test — the definitive test for non-classic CAH; a stimulated 17-OHP above 10 ng/mL is diagnostic
4. Genetic testing — confirms the specific CYP21A2 mutation and guides family counselling

Treatment options

Treatment aims to replace the cortisol the adrenal glands cannot make and to suppress the ACTH excess that drives androgen overproduction.

Glucocorticoid replacement is the cornerstone. Hydrocortisone is preferred in children because it has a shorter duration of action and is less likely to suppress growth than prednisone or dexamethasone. Adults may use any of the three, titrated to the lowest effective dose. All patients with CAH require stress dosing — doubling or tripling their glucocorticoid dose during fever, surgery, or serious illness — to prevent adrenal crisis, exactly as in Addison's disease.

Mineralocorticoid replacement (fludrocortisone) is required in salt-wasting CAH to maintain sodium balance and blood pressure. Newborns also need supplemental dietary salt until they can reliably signal thirst.

Monitoring throughout childhood includes regular measurement of growth velocity, bone age X-rays, and androgen levels to ensure androgens are adequately suppressed without over-treating with glucocorticoids, which carries its own risks (growth suppression, weight gain, bone loss).

Surgical management of ambiguous genitalia in females with classic CAH is sometimes considered but is a complex, ethically nuanced decision that requires multidisciplinary input from endocrinology, urology, psychology, and the family. Timing and extent of any intervention should not be rushed.

For adults with non-classic CAH who have mild symptoms, treatment may not be necessary. When symptoms are bothersome — irregular cycles, hirsutism, fertility difficulties — low-dose glucocorticoid therapy or, in some cases, oral contraceptives or anti-androgens may be appropriate depending on the individual's goals.

When to see a clinician in Canada

Seek prompt medical attention if:

• A newborn screening result flags elevated 17-OHP, or a newborn has ambiguous genitalia
• A newborn or infant develops vomiting, poor feeding, or signs of dehydration in the first weeks of life — this may be a salt-wasting crisis requiring emergency care
• A child shows premature pubic hair, body odour, or acne before age 8 (girls) or 9 (boys)
• A woman has irregular periods, hirsutism, or acne alongside a family history of CAH — non-classic CAH is frequently undiagnosed in this group
• An adult has unexplained fertility difficulties with signs of androgen excess
• A person with known CAH becomes unwell, is vomiting, or cannot take their oral medication — this is a potential adrenal crisis and warrants emergency assessment

Canadian patients can access endocrinology referrals through their family physician or, for adults seeking initial hormone assessment, through virtual care platforms such as Felix, Maple, or Cleo, though confirmed or suspected CAH requires in-person specialist follow-up given the complexity of monitoring.

Limitations and open questions

Research is still emerging on several fronts. Optimal glucocorticoid dosing strategies — particularly how to mimic the normal diurnal cortisol rhythm — remain an active area of investigation, with modified-release hydrocortisone formulations under study but not yet widely available in Canada. The long-term cardiovascular and metabolic consequences of lifelong glucocorticoid exposure are not fully characterized. For non-classic CAH specifically, there is no consensus on which patients benefit from treatment versus watchful waiting, and evidence on fertility outcomes with different treatment approaches is limited. The ethics and long-term outcomes of early genital surgery in females with classic CAH remain actively debated in the medical and patient communities. Health Canada has not issued a standalone CAH management guideline; Canadian clinicians generally follow the 2018 Endocrine Society Clinical Practice Guideline. Genetic counselling access varies by province, and wait times for pediatric endocrinology in some regions can be lengthy.