How do you diagnose and manage a patient with suspected nontypical 11-beta hydroxylase (11-beta hydroxylase) adrenal hyperplasia, presenting with hypertension and hypokalemia?

Diagnosing Non-Classical 11β-Hydroxylase Deficiency

In patients presenting with hypertension and hypokalemia, diagnose non-classical 11β-hydroxylase deficiency by measuring elevated serum 11-deoxycortisol and 11-deoxycorticosterone levels alongside increased adrenal androgens (testosterone, androstenedione), with confirmatory genetic testing of the CYP11B1 gene. 1, 2

Clinical Presentation to Recognize

Non-classical 11β-hydroxylase deficiency presents distinctly from typical primary adrenal insufficiency and requires high clinical suspicion in specific scenarios:

• Early-onset hypertension (often juvenile or young adult onset) with hypokalemia and suppressed plasma renin activity (PRA) 1, 3
• Hyperandrogenism in females: menstrual disorders, hirsutism, premature adrenarche 1, 4
• Bilateral adrenal hyperplasia on imaging (CT or MRI) 3, 5
• Absence of typical Cushing's features despite elevated androgens 1

Critical pitfall: This condition is frequently misdiagnosed as polycystic ovary syndrome (PCOS) or essential hypertension because symptoms are mild compared to classical 11β-hydroxylase deficiency 1, 4

Diagnostic Algorithm

Step 1: Initial Biochemical Screening

Measure the following hormones simultaneously in the morning:

• Elevated 11-deoxycortisol (the hallmark finding) 3, 2
• Elevated 11-deoxycorticosterone (DOC) 2
• Elevated ACTH 3
• Elevated 17-hydroxyprogesterone (17-OHP) 3
• Elevated androgens: testosterone and androstenedione 3, 2
• Suppressed plasma renin activity (PRA) 3, 2
• Low-normal or suppressed aldosterone 3
• Serum potassium (typically low) 3, 2

Step 2: Imaging Evaluation

• Adrenal CT scan to identify bilateral nodular adrenal hyperplasia 3, 5
• This distinguishes the condition from unilateral adenomas causing hyperaldosteronism 6

Step 3: Confirmatory Genetic Testing

• CYP11B1 gene sequencing of all exons to identify pathogenic variants 1, 3, 5
• Mutations are race-specific and concentrated in exons 3 and 8, with exon 3 mutations predominantly associated with non-classical disease 1
• Both compound heterozygous and homozygous mutations can cause non-classical phenotypes 1, 3

Key Diagnostic Distinctions

Versus Primary Aldosteronism: While both present with hypertension and hypokalemia, 11β-hydroxylase deficiency shows elevated (not suppressed) ACTH, bilateral (not unilateral) adrenal enlargement, and hyperandrogenism 6, 3. The plasma aldosterone-to-renin ratio pattern differs—aldosterone is low-normal in 11β-hydroxylase deficiency but elevated in primary aldosteronism 6, 3.

Versus PCOS: Non-classical 11β-hydroxylase deficiency shows hypertension with suppressed renin, elevated 11-deoxycortisol, and bilateral adrenal hyperplasia—features absent in PCOS 1, 4. However, genetic studies confirm that 11β-hydroxylase deficiency is not a significant cause of hyperandrogenism in women presenting to reproductive endocrinology clinics 4.

Management After Diagnosis

Once confirmed, initiate treatment with:

• Hydrocortisone 15-25 mg daily in divided doses to suppress ACTH-driven androgen excess 1, 2
• Spironolactone or other antihypertensive agents for blood pressure control 1
• Monitor for adequate suppression of androgens while avoiding glucocorticoid excess 2

Important caveat: Early diagnosis prevents irreversible organ damage from chronic hypertension and hyperandrogenism, including left ventricular hypertrophy and arterial sclerosis 1, 5. Hypertension develops in approximately 50% of patients during follow-up, with median onset around age 9 years in pediatric cohorts 5.