Glucocorticoid resistance syndrome: let’s give it a thought

In recognition of Professor George P. Chrousos' extensive and ground-breaking research work in this field, it has been proposed that the term “Chrousos Syndrome” is used in place of “Primary Generalized Familial or Sporadic Glucocorticoid Resistance” [1]. The first patient presenting with glucocorticoid resistance syndrome was described in 1976, in whom high blood pressure was incidentally found in association with hypokalemia and high urinary free cortisol reaching 30–40 times the normal reference values [2].

Glucocorticoids (GC) such as cortisol regulate multiple physiological functions, notably those involved in development, metabolism, inflammatory processes and stress, and exert their effects upon binding to the glucocorticoid receptor (GR, encoded by NR3C1 gene in humans). Generalized glucocorticoid resistance syndrome, due to GR loss-of-function mutations, may be related to the impairment of one of the GC signalling steps. To date, 31 NR3C1 loss-of-function mutations have been reported in patients presenting with various clinical signs such as hypertension, adrenal hyperplasia, hirsutism or metabolic disorders associated with biological hypercortisolism but without Cushing syndrome signs and no negative regulatory feedback loop on the hypothalamic–pituitary–adrenal axis. The main signs at presentation are very variable from resistant hypertension, bilateral adrenal hyperplasia likely related to increased ACTH levels but not exclusively, hirsutism to isolated renin–angiotensin–aldosterone system abnormalities in a context of 11βHSD2 deficiency [3].

26-year-old female patient child of a consanguious marriage came with complaints of excessive facial hair growth since last 10 years, poor development of breasts and occasional episodes of headache since last 10 years. She was diagnosed to have hypertension and was taking tablet amlodipine 5 mg (not regularly). She had history of tuberculosis at age of 14, took antitubercular medications for 9 months. At 15 years of age patient had an episode of myalgia and weakness of all 4 limbs (Sudden onset Quadriparesis). She was diagnosed to have renal potassium loss as her trans-tubular potassium gradient was 14, Serum Potassium—1.9 mmol/l, Urine potassium—27.8 mEq/l, Plasma osmolality—315 mOsm/l, Urine osmolality—350 mOsm/l. Her echocardiogram showed U waves, ST segment depression with T-wave inversion and Q-T prolongation. Patient was started on oral potassium supplements and was still on Syrup K-sol.

Generalized glucocorticoid resistance syndrome is defined by an absence of overt Cushing’s syndrome signs (no skin weakness, muscle atrophy, or osteoporosis), associated with biological hypercortisolism consisting of high urinary free cortisol (UFC) and an absence of negative feedback loop of cortisol on HPA, defined as 8-AM cortisol level > 50 nmol/L after overnight 1 mg dexamethasone suppression test (DST) [4].

Differential diagnosis of generalized glucocorticoid resistance includes: (1) mild forms of Cushing's disease, in which hypercortisolism is accompanied by normal or mildly elevated ACTH concentrations; (2) pseudo-Cushing's states, such as generalized anxiety disorder and melancholic depression; (3) conditions associated with elevated serum concentrations of corticosteroid-binding globulin, such as normal pregnancy and estrogen treatment; (4) essential hypertension, hyperaldosteronism, and other causes of mineralocorticoid-induced hypertension; and (5) other causes of hyperandrogenism or virilization, such as idiopathic hirsutism, polycystic ovarian syndrome, and congenital adrenal hyperplasia (CAH).

The aim of treatment is to suppress the excess secretion of ACTH, thereby suppressing the increased production of adrenal steroids with mineralocorticoid and androgenic activity. Treatment involves administration of high doses of mineralocorticoid-sparing synthetic glucocorticoids, such as dexamethasone (1–3 mg/d). Long-term dexamethasone treatment should be carefully titrated according to the clinical manifestations and biochemical profile of the affected subjects [5].

If one suspects Chrousos syndrome in clinical practice, a detailed personal and family history should be obtained, meanwhile physical examination should include an assessment for signs of mineralocorticoid and/or androgen excess. Suspected patients should then undergo a detailed endocrinologic evaluation with particular emphasis on the measurement of serum cortisol concentrations and determination of the 24-h urinary free cortisol (UFC) excretion on 2 or 3 consecutive days. Diagnosis of Chrousos syndrome is confirmed by sequencing of the coding region of the NR3C1 gene. Endocrinologist evaluation and subsequent treatment should be sought for in these cases.