What is the diagnosis and treatment for a patient with elevated 17-hydroxyprogesterone (17-OHP) and low random cortisol levels, suggestive of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency?

Diagnosis: Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency

The combination of elevated 17-hydroxyprogesterone and low random cortisol is diagnostic of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, which accounts for approximately 90% of all CAH cases. 1, 2

Confirmatory Diagnostic Testing

Obtain paired morning (8 AM) serum cortisol and plasma ACTH measurements immediately to confirm primary adrenal insufficiency, which will show low cortisol with markedly elevated ACTH. 3, 4

Key Diagnostic Thresholds:

• Basal cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH is diagnostic of primary adrenal insufficiency 3, 4
• 17-hydroxyprogesterone levels will be markedly elevated (typically >200 ng/dL in classic forms, often exceeding 1000 ng/dL) 5, 6
• ACTH stimulation test (if needed for equivocal cases): Administer 0.25 mg cosyntropin IM or IV, with peak cortisol <500 nmol/L (<18 μg/dL) at 30-60 minutes confirming adrenal insufficiency 3, 4

Additional Laboratory Findings to Expect:

• Hyponatremia (present in 90% of cases) due to aldosterone deficiency and impaired free water clearance 3, 7
• Hyperkalemia (present in only ~50% of cases), so its absence does not exclude the diagnosis 3, 7
• Elevated plasma renin activity with low aldosterone in salt-wasting forms 3, 7
• Elevated androstenedione (correlates strongly with 17-hydroxyprogesterone levels) 5
• Possible mild hypercalcemia (10-20% of cases), eosinophilia, lymphocytosis, and elevated liver transaminases 3, 7

Etiologic Workup

Measure 21-hydroxylase (anti-adrenal) autoantibodies first to distinguish autoimmune adrenal insufficiency from CAH—these will be negative in CAH. 3, 4

If autoantibodies are negative, the elevated 17-hydroxyprogesterone confirms 21-hydroxylase deficiency CAH without need for genetic testing in most cases. 1, 2

Consider measuring additional steroids if diagnosis remains uncertain:

• 21-deoxycortisol (will be elevated and correlates with 17-hydroxyprogesterone in 21-hydroxylase deficiency) 6
• 11-deoxycortisol (to exclude 11β-hydroxylase deficiency, which accounts for 3-5% of CAH cases and may be misdiagnosed as 21-hydroxylase deficiency) 6

Immediate Treatment Protocol

Critical Pitfall to Avoid:

Never delay treatment of suspected acute adrenal crisis for diagnostic testing—if the patient is clinically unstable with hypotension, vomiting, or collapse, administer IV hydrocortisone 100 mg immediately plus 0.9% saline infusion at 1 L/hour. 3, 4

Draw blood for cortisol and ACTH before treatment if possible, but do not wait for results. 3, 4

Chronic Replacement Therapy

Glucocorticoid Replacement:

Administer hydrocortisone 15-25 mg daily in divided doses, with the largest dose given in the morning (between 0400-0800h when ACTH activity peaks) and the last dose no less than 6 hours before bedtime. 3, 5

• Alternative regimens: Cortisone acetate 25-37.5 mg daily or prednisolone 4-5 mg daily 3, 4
• Timing is critical: Hydrocortisone should be administered during the period of increased hypothalamic-pituitary-adrenal axis activity (0400-1600h) to suppress early morning ACTH surges 5

Mineralocorticoid Replacement (for salt-wasting forms):

Administer fludrocortisone 0.1-0.2 mg daily in conjunction with glucocorticoid therapy. 8

• Standard dose: 0.1 mg daily, though dosing from 0.1 mg three times weekly to 0.2 mg daily may be employed 8
• If transient hypertension develops, reduce dose to 0.05 mg daily 8

Monitoring Strategy

Biochemical Monitoring:

Measure morning (pre-dose) 17-hydroxyprogesterone and androstenedione levels as these correlate strongly and reflect adequacy of suppression. 5

• Target 17-hydroxyprogesterone: Upper normal range to 2-3 times upper limit of normal (over-suppression increases glucocorticoid side effects) 5, 9
• Morning androstenedione correlates strongly with integrated 17-hydroxyprogesterone concentrations (r = 0.81) and is useful for monitoring 5

Clinical Monitoring:

Monitor body mass, waist circumference, blood pressure, glucose, lipids, and bone mineral density by DEXA scan regularly as patients with classic CAH have increased risk of obesity, insulin resistance, metabolic syndrome, and osteoporosis from chronic glucocorticoid therapy. 9

Important Monitoring Pitfall:

Blood investigations are only complementary to overall assessment—primary evaluation should be based on growth (in children), pubertal progress, signs of hyperandrogenism in females, and glucocorticoid side effects. 5, 9

Patient Education Requirements

All patients must:

• Wear medical alert identification jewelry and carry a steroid emergency card 3, 4
• Receive education on stress-dose glucocorticoids (double or triple maintenance dose during illness, injury, or surgery) 3, 4
• Have supplies for self-injection of parenteral hydrocortisone for emergency use 3
• Undergo endocrine consultation before any surgical procedures for stress-dose planning 4

Long-Term Considerations

Patients with CAH require lifelong multidisciplinary care involving endocrinology, and potentially gynecology (for females with fertility concerns or hyperandrogenism), urology/andrology, and psychology. 9

Screen annually for associated autoimmune conditions including thyroid dysfunction, diabetes, pernicious anemia, and celiac disease, particularly if 21-hydroxylase autoantibodies were positive. 4