Glucocorticoid Resistance Syndrome

Glucocorticoid resistance syndrome (Chrousos syndrome) is a rare disorder of reduced tissue sensitivity to cortisol, caused by variants in the glucocorticoid receptor gene (NR3C1). It is usually autosomal dominant, with a few recessive cases.

Reduced receptor function weakens negative feedback, so ACTH and cortisol rise, with excess adrenal androgens and mineralocorticoids. The patient has no Cushingoid features despite high cortisol.

Severity varies from asymptomatic (found by chance) to severe, with hypertension, hypokalaemia and hyperandrogenism.

Pathophysiology.

Variants reduce receptor number, ligand binding, nuclear translocation or gene regulation. The hypothalamic-pituitary-adrenal axis then sets a higher cortisol level to compensate.

High ACTH drives adrenal androgens and deoxycorticosterone and corticosterone, which act on the mineralocorticoid receptor to cause hypertension and hypokalaemia.

• Fatigue, hypertension and hypokalaemic alkalosis.
• Hyperandrogenism: hirsutism, acne, male pattern balding and oligomenorrhoea or infertility in women, early adrenarche in children, and oligospermia in men.
• Adrenal enlargement on imaging. Many family members are well.

Red flags.

• Severe hypertension or hypokalaemia.
• Precocious puberty or virilisation in a child.

• Raised 24-hour urinary free cortisol and morning serum cortisol with normal diurnal rhythm, and raised ACTH or normal ACTH, but no Cushing features.
• 1 mg dexamethasone test: cortisol is not suppressed below 50 nmol/L. Dexamethasone 1 to 3 mg for 2 days suppresses cortisol only partly.
• Androgens (androstenedione, DHEAS, testosterone) raised, with raised deoxycorticosterone, potassium low and renin low or normal.
• NR3C1 sequencing confirms the diagnosis. Adrenal CT or MRI may show bilateral hyperplasia.

Differential diagnosis.

• Cushing syndrome and Cushing disease (clinical features present).
• Primary aldosteronism, congenital adrenal hyperplasia (11-beta hydroxylase and 17-alpha hydroxylase deficiency) and apparent mineralocorticoid excess.
• Polycystic ovary syndrome, and depression with raised cortisol.

• Asymptomatic patients with mild disease need no treatment.
• Symptomatic patients: dexamethasone 0.25 to 3 mg at night, titrated to suppress ACTH, androgens and mineralocorticoids while avoiding Cushingoid effects. Use the lowest effective dose. Hydrocortisone and prednisolone are not used because they increase mineralocorticoid effects.
• Persistent hypertension or hypokalaemia: spironolactone 50 to 200 mg daily or eplerenone 50 to 100 mg daily, with potassium supplements if needed.
• Hyperandrogenism in women: dexamethasone, spironolactone 100 to 200 mg daily or combined oral contraceptive.
• Genetic counselling: 50% risk for children in dominant disease.

Special groups. Pregnancy: dexamethasone crosses the placenta, so adjust treatment in a specialist centre. Children: treat precocious adrenarche and monitor growth.

Monitoring. Blood pressure, potassium, ACTH, androgens and cortisol every 3 to 6 months at first, bone density and glucose yearly on dexamethasone.

Referral and escalation. Endocrinology with clinical genetics.