Primary Pigmented Nodular Adrenocortical Disease

Primary pigmented nodular adrenocortical disease is a rare cause of ACTH-independent Cushing syndrome in children and young adults, with small pigmented cortical micronodules (under 4 mm) and atrophic internodular cortex.

It occurs in the Carney complex (PRKAR1A variants in most families, autosomal dominant) or alone (PDE11A, PDE8B variants). Most patients with Carney complex have adrenal pathology, and a minority have overt Cushing syndrome.

Presentation is usually in the second to third decade, and it is more common in women. Growth failure or cyclical cortisol excess may occur.

Pathophysiology.

Loss of PRKAR1A function raises protein kinase A activity, driving cortisol production and cell growth despite low ACTH. Pigment (lipofuscin) gives the nodules a dark colour.

Glucocorticoid paradoxically stimulates cortisol production in the nodules.

• Cushingoid features, often with growth failure and weight gain in children, osteoporosis and mood disorder.
• Carney complex features: spotty skin pigmentation, cardiac and cutaneous myxomas, schwannoma, growth hormone excess, thyroid nodules and large cell calcifying Sertoli cell tumours.
• Features may be intermittent.

Red flags.

• Cardiac murmur, embolic event or arrhythmia (cardiac myxoma).
• Rapid growth or visual loss.

• Confirm hypercortisolism with late night salivary or urinary free cortisol and 1 mg dexamethasone suppression (cortisol over 50 nmol/L, 1.8 micrograms/dL). ACTH suppressed (under 10 ng/L, 2 pmol/L).
• Paradoxical increase in urinary free cortisol of over 50% on the 6th day of the Liddle test (dexamethasone 2 mg daily for 2 days then 8 mg daily for 2 days).
• CT: normal or small adrenals with a beaded outline or small nodules. The glands may look normal.
• PRKAR1A sequencing and family screening. Echocardiography, pituitary hormones and IGF-1, thyroid and testicular ultrasound, and skin examination.

Differential diagnosis.

• Cushing disease and ectopic ACTH syndrome.
• Adrenal adenoma or carcinoma and primary bilateral macronodular adrenal hyperplasia.
• McCune-Albright syndrome and MEN1.

• Bilateral adrenalectomy (laparoscopic) for overt disease, with lifelong hydrocortisone 15 to 25 mg daily in two or three divided doses (children 10 to 15 mg/m2 daily in three divided doses) and fludrocortisone 0.05 to 0.2 mg daily. Unilateral adrenalectomy leads to recurrence.
• Short term cortisol control while awaiting surgery: ketoconazole 200 mg twice daily or metyrapone 250 mg three times daily.
• Provide sick day rules: double the dose in illness and give hydrocortisone 100 mg intramuscularly or intravenously for vomiting or collapse.
• Treat other Carney complex features (cardiac myxoma excision, growth hormone excess).

Special groups. Children: growth and pubertal monitoring, and weight based replacement. Genetic counselling for families (50% inheritance risk).

Monitoring. Annual echocardiography from early childhood, thyroid and testicular ultrasound, IGF-1, and adrenal replacement review.

Referral and escalation. Endocrinology with paediatric, adrenal surgery and clinical genetics services.