What are the symptoms and treatment of Congenital Adrenal Hyperplasia (CAH)?

Congenital Adrenal Hyperplasia: Clinical Manifestations and Management

Clinical Presentation and Symptoms

Congenital adrenal hyperplasia (CAH) presents with a constellation of symptoms related to cortisol deficiency, aldosterone deficiency (in most cases), and androgen excess, with manifestations varying by severity and age at presentation.

Classic Salt-Wasting Form (Most Severe)

• Life-threatening adrenal crisis can occur within the first weeks of life, presenting with shock, hyponatremia, and hyperkalemia—this is a medical emergency requiring immediate recognition 1.
• Hyponatremia is present in 90% of newly diagnosed cases, though hyperkalemia occurs in only approximately 50% of patients 2.
• Inability to regulate electrolyte levels leads to potential cardiovascular collapse if untreated 1.
• Female infants (46 XX genotype) present with ambiguous genitalia and virilization at birth due to prenatal androgen exposure 1, 3.
• Male infants may appear phenotypically normal at birth but develop adrenal crisis, making diagnosis more challenging 1.

Simple Virilizing Form (Less Severe)

• Virilization occurs in females without the salt-wasting crisis 4, 5.
• Premature development of pubic hair (premature adrenarche) in both sexes 3.
• Advanced bone age and accelerated linear growth velocity in childhood 3.
• Early beard growth and acne in males 3.
• Diminished final adult height due to premature epiphyseal closure 6, 3.

Non-Classic Form (Mildest)

• Presents later in childhood, puberty, or adulthood rather than in infancy 4, 3.
• Earlier onset of puberty compared to unaffected individuals 5.
• Hyperandrogenism symptoms in females: hirsutism, severe cystic acne, temporal baldness, and menstrual irregularities 3.
• Delayed menarche or secondary amenorrhea 3.
• Polycystic ovary syndrome may develop 3.
• Males may present with oligozoospermia or diminished fertility 3.

Specific Enzyme Deficiency Variants

• 11β-hydroxylase deficiency: presents with hypertension and hypokalemia alongside virilization 1, 7.
• 17α-hydroxylase deficiency: causes incomplete masculinization in males and primary amenorrhea in females 1.

Critical Diagnostic Considerations

Emergency Recognition

• A newborn with male phenotype and bilateral nonpalpable testes must be evaluated immediately for possible 46 XX CAH—this represents a genetic female with severe virilization and requires urgent assessment 1.
• Do not circumcise until workup is complete, even with normal-appearing penis 1.
• Failure to diagnose can result in life-threatening adrenal crisis with shock, hyponatremia, and hyperkalemia 1.

Diagnostic Testing

• Morning serum cortisol and plasma ACTH are first-line tests, with low cortisol and elevated ACTH indicating primary adrenal insufficiency 8.
• Cosyntropin (ACTH) stimulation test: administer 0.25 mg with cortisol measurements at baseline and 30 minutes; peak cortisol <500 nmol/L (<18 μg/dL) confirms adrenal insufficiency 8.
• Elevated 17-hydroxyprogesterone (17-OHP) levels confirm 21-hydroxylase deficiency 3.
• Molecular genetic analysis confirms diagnosis and identifies specific mutations 3.
• For 11β-hydroxylase deficiency: elevated deoxycorticosterone (DOC) and corticosterone with hypertension and hypokalemia 1, 7.

Treatment Approach

Acute Management (Adrenal Crisis)

• Immediate IV hydrocortisone 100 mg bolus plus 0.9% saline infusion at 1 L/hour—never delay treatment for diagnostic testing if patient is unstable 8, 2.
• Draw blood for cortisol and ACTH before treatment if possible, but do not delay therapy 8.
• Repeat hydrocortisone 100 mg every 6 hours until stabilized 1.

Chronic Glucocorticoid Replacement

• Hydrocortisone 15-25 mg daily in divided doses is the preferred glucocorticoid, typically given as 10 mg at 7:00 AM, 5 mg at 12:00 PM, and 2.5-5 mg at 4:00 PM to mimic physiological cortisol secretion 8.
• Alternative regimens include cortisone acetate 25-37.5 mg daily or prednisolone 4-5 mg daily 1, 8.
• During pregnancy, increase hydrocortisone by 2.5-10 mg daily in the third trimester due to increased cortisol requirements 1.
• During delivery, give 100 mg IV hydrocortisone bolus, repeated every 6 hours as needed 1.

Mineralocorticoid Replacement (Primary Adrenal Insufficiency Only)

• Fludrocortisone 50-200 µg daily (up to 500 µg in children, young adults, or late pregnancy) 1, 8.
• Unrestricted sodium salt intake is essential—patients should eat salty foods without restriction and avoid potassium-containing salts 1.
• Monitor for adequacy by assessing salt cravings, orthostatic blood pressure changes, and peripheral edema 1.
• Increase dose during late pregnancy due to progesterone's anti-mineralocorticoid effects 1.

Androgen Suppression and Fertility Management

• Adequate glucocorticoid dosing suppresses excess ACTH and reduces adrenal androgen production 6, 3.
• In females with persistent hyperandrogenism despite optimized glucocorticoid therapy, consider DHEA 25 mg daily for 6 months as trial 1.
• Subfertility is common in both sexes: pregnancy rates depend on severity (salt-wasting < simple virilizing < non-classic) 5.
• Males may develop testicular adrenal rest tumors requiring glucocorticoid optimization 5.
• Symptoms of androgen excess typically reverse within 3 months of appropriate glucocorticoid treatment 3.

Critical Management Pitfalls to Avoid

• Never rely on electrolyte abnormalities alone—hyperkalemia is absent in 50% of cases, and vomiting can cause hypokalemia that masks expected hyperkalemia 8, 2.
• Avoid diuretics, acetazolamide, NSAIDs, and liquorice as they interact with fludrocortisone 1.
• Grapefruit juice potentiates mineralocorticoid effects and should be avoided 1.
• Do not stop mineralocorticoid replacement to treat hypertension—add a vasodilator instead and consider dose reduction 1.
• Under-replacement of mineralocorticoids is common and may be compensated by glucocorticoid over-replacement, predisposing to adrenal crises 1.

Patient Education and Long-Term Monitoring

• All patients must wear medical alert identification indicating adrenal insufficiency 8.
• Provide stress-dose education: double or triple dose during illness, fever, or physical stress 8.
• Prescribe hydrocortisone 100 mg IM injection kit with self-injection training for emergencies 8.
• Monitor growth, bone age, and pubertal development in children to optimize final adult height 6, 5.
• Screen annually for associated autoimmune conditions including thyroid disease, diabetes, pernicious anemia, and celiac disease 8.
• Mandatory endocrine consultation for newly diagnosed patients, pre-operative planning, and recurrent adrenal crises 8.