Glucocorticoid Resistance, Generalized

A number sign (#) is used with this entry because generalized glucocorticoid resistance (GCCR) is caused by heterozygous mutation in the glucocorticoid receptor gene (NR3C1, GCCR; 138040) on chromosome 5q31.

Description

Generalized glucocorticoid resistance is an autosomal dominant disease characterized by increased plasma cortisol concentration and high urinary free cortisol, resistance to adrenal suppression by dexamethasone, and the absence of clinical stigmata of Cushing syndrome. The clinical expression of the disease is variable. Common features include hypoglycemia, hypertension, and metabolic alkalosis. In females, overproduction of adrenal androgens has been associated with infertility, male-pattern baldness, hirsutism, and menstrual irregularities. Other features include chronic fatigue and profound anxiety (summary by Chrousos et al., 1983; Donner et al., 2013).

Clinical Features

Vingerhoeds et al. (1976) reported a case of cortisol resistance. High levels of cortisol (without stigmata of Cushing syndrome), resistance of the hypothalamic-pituitary-adrenal axis to dexamethasone, and an affinity defect of the glucocorticoid receptor characterized the disorder. Chrousos et al. (1982) restudied the family reported by Vingerhoeds et al. (1976). A man who was presumably homozygous had mineralocorticoid excess resulting in hypertension, hypokalemia, and metabolic alkalosis. One of his brothers, who had severe hypertension and died of a cerebrovascular accident at age 54, may also have been homozygous. Another brother and his son were apparently heterozygous; they showed slightly elevated 24-hour mean plasma cortisol levels and increased urinary free cortisol. Lipsett et al. (1986) provided further follow-up on the 4-generation family originally reported by Vingerhoeds et al. (1976). Autosomal dominant inheritance of glucocorticoid resistance was clearly demonstrated. Lipsett et al. (1986) believed that a mutation in the glucocorticoid receptor was responsible, although other explanations could be invoked. The single homozygote in the family was the proband; the other persons with elevated plasma cortisol levels and increased urinary free cortisol represented heterozygotes. The parents of the proband descended from families with consanguinity that occurred before the 16th century. The 2 parental families had lived in close proximity for many generations. This cortisol resistance is probably the rarest cause of treatable hypertension yet described.

Affected mother and son with primary cortisol resistance and a reduction in glucocorticoid receptors were reported by Iida et al. (1985).

Bronnegard et al. (1986) described a woman with receptor-mediated resistance to cortisol as indicated by elevated 24-hour mean plasma cortisol levels and increased free urinary cortisol. Plasma ACTH concentrations were normal but she was resistant to adrenal suppression by dexamethasone. No stigmata of Cushing syndrome were present. The patient had symptoms of pronounced fatigue. Menopause had occurred at age 43. The patient's only child, a son, aged 29 years, had periods of inexplicable fatigue that had made him stay home from school and work. Because of the extreme fatigue that led to the mother's working only half-time, Addison's disease was suspected, but rather than hypocortisolism, elevation of urinary cortisol values was found. Bronnegard et al. (1986) found that the end-organ insensitivity to cortisol was not due to decreased concentration or ligand affinity of the receptor. The woman and her son instead showed an increased thermolability of the cortisol receptor, a phenomenon also observed with the androgen receptor in patients with the testicular feminization syndrome (300068).

Lamberts et al. (1986) described cortisol resistance in a 26-year-old woman with hirsutism, mild virilization, and menstrual difficulties. They thought that the abnormality was autosomal dominant because her father and 2 brothers had increased plasma cortisol concentrations that did not suppress normally in response to dexamethasone. No hypertension or hypokalemic alkalosis was present. The proband had male-pattern scalp baldness.

Nawata et al. (1987) studied a 27-year-old woman with glucocorticoid resistance. She was initially thought to have Cushing disease, based on high plasma ACTH and serum cortisol levels, increased urinary cortisol secretion, resistance to adrenal suppression with dexamethasone, and bilateral adrenal hyperplasia by computed tomography and scintigraphy; however, she had no clinical signs or symptoms of Cushing syndrome. Laboratory studies indicated that the patient's glucocorticoid resistance was due to a decrease in the affinity of the receptor for glucocorticoids and a decrease in the binding of the GCCR complex to DNA.

Charmandari et al. (2008) reviewed the clinical aspects, molecular mechanisms, and implications of primary generalized glucocorticoid resistance. They noted that the clinical spectrum is broad, ranging from asymptomatic to severe cases of hyperandrogenism, fatigue, and/or mineralocorticoid excess. Mutations in the GCCR gene resulting in the disorder impair glucocorticoid signal transduction and reduce tissue sensitivity to glucocorticoids. A consequent increase in the activity of the hypothalamic-pituitary-adrenal axis compensates for the reduced sensitivity of peripheral tissues to glucocorticoids at the expense of ACTH hypersecretion-related pathology. The study of functional defects of GCCR mutants highlighted the importance of integrated cellular and molecular signaling mechanisms for maintaining homeostasis and preserving normal physiology.

Molecular Genetics

In affected members of the kindred originally reported by Vingerhoeds et al. (1976) with generalized glucocorticoid deficiency, Hurley et al. (1991) identified a heterozygous missense mutation in the GCR gene (D641V; 138040.0001).

In all 3 affected members of a Dutch kindred with glucocorticoid resistance, Karl et al. (1993) identified heterozygosity for a 4-bp deletion in the GCR gene (138040.0002).

Bray and Cotton (2003) stated that a total of 15 missense, 3 nonsense, 3 frameshift, 1 splice site, and 2 alternatively spliced mutations had been reported in the NR3C1 gene to be associated with glucocorticoid resistance. Sixteen polymorphisms in the gene had also been reported.

Heterogeneity

Huizenga et al. (2000) described 5 patients with biochemical and clinical cortisol resistance. They found alterations in receptor number or ligand affinity and/or the ability of dexamethasone to inhibit mitogen-induced cell proliferation. To investigate the molecular defects leading to the clinical and biochemical pictures in these patients, they screened the GCCR gene using PCR-SSCP sequence analysis. No GCCR gene alterations were found in these patients. The authors concluded that alterations somewhere in the cascade of events starting with ligand binding to the GCCR protein, and finally resulting in the regulation of the expression of glucocorticoid-responsive genes, or postreceptor defects or interactions with other nuclear factors, form the pathophysiologic basis of cortisol resistance in these patients.

Pathogenesis

Generalized glucocorticoid resistance is caused by impaired cortisol signaling. This defect results in compensatory activation of the hypothalamic-pituitary adrenal axis, which leads to increased secretion of hypothalamic corticotropin-releasing hormone (CRH) and elevated secretion of the circulating ACTH from the pituitary gland. The excess ACTH secretion, in turn, results in increased secretion of cortisol, the adrenal mineralocorticoids deoxycorticosterone and corticosterone, and adrenal steroids with androgenic activity (summary by Donner et al., 2013).

Evolution

Two New World primates, the squirrel monkey and the marmoset, have markedly elevated plasma cortisol levels without physiologic evidence of glucocorticoid hormone excess. Chrousos et al. (1982) showed that their hypothalamic-pituitary-adrenal axis is resistant to suppression by dexamethasone. They studied glucocorticoid receptors in circulating monocytes and cultured skin fibroblasts of New and Old World monkeys and found that, although the receptor content was the same in all species, the 2 New World species had markedly decreased binding affinity for dexamethasone. The presumed mutation must have occurred after bifurcation of the Old and New World primates (about 60 Myr ago) and before diversion of the 2 New World species (about 15 Myr ago). A difference between the disorder in man with an affinity defect of the glucocorticoid receptor and the state in New World monkeys is that in the severe form of the human disease, sodium-retaining corticoids (corticosterone and deoxycorticosterone) are elevated many-fold, producing hypertension and hypokalemic alkalosis. The mineralocorticoid overproduction, which does not occur in the New World monkeys, is probably due to corticotropin hyperstimulation of the adrenal cortex.

Animal Model

Examples of resistance to cortisol are known; the guinea pig is a 'corticoresistant' species (Vingerhoeds et al., 1976).