GRL DEFICIENCY, INCLUDED
GCR DEFICIENCY, INCLUDED
NR3C1 GLUCOCORTICOID RECEPTOR DEFICIENCY, INCLUDED
NUCLEAR RECEPTOR SUBFAMILY 3, GROUP C, MEMBER 1
PSEUDOHERMAPHRODITISM, FEMALE, WITH HYPOKALEMIA, DUE TO GLUCOCORTICOID RESISTANCE, INCLUDED
GCCR DEFICIENCY, INCLUDED
GLUCOCORTICOID RESISTANCE, INCLUDED
CORTISOL RESISTANCE FROM GLUCOCORTICOID RECEPTOR DEFECT, INCLUDED
BODY COMPOSITION, BENEFICIAL, INCLUDED
GRL
GCCR
GCR
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 ... 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 decreased 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. Rather the woman and her son 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 the syndrome of 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. - Corticotrophinomas As cortisol resistance can be caused by genetic abnormalities in the GRL gene, Huizenga et al. (1998) investigated whether the insensitivity of corticotropinomas to cortisol is also caused by de novo GRL mutations. Except for 1 silent point mutation, they did not identify mutations in the GRL gene in leukocytes or corticotropinomas from 22 patients with Cushing disease. Of the 22 patients, 18 were heterozygous for at least 1 polymorphism, and 6 of the 18 had loss of heterozygosity (LOH) in the tumor DNA. They concluded that LOH at the GRL locus is a relatively frequent phenomenon in pituitary adenomas of patients with Cushing disease and that this may explain the relative resistance of the adenoma cells to the inhibitory feedback action of cortisol on ACTH secretion.
Bray and Cotton (2003) reported 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 associated with glucocorticoid resistance, as well as 16 ... Bray and Cotton (2003) reported 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 associated with glucocorticoid resistance, as well as 16 polymorphisms. Stevens et al. (2004) tested the potential involvement of the GCCR gene in mediating glucocorticoid sensitivity using haplotype analysis and a low-dose dexamethasone suppression test. Linkage disequilibrium across the GCCR gene was determined in 216 Caucasians from the United Kingdom, and 116 had a 0.25-mg overnight dexamethasone suppression test. Very strong linkage disequilibrium was observed across the GCCR gene, with only 4 haplotypes accounting for 95% of those observed. Haplotype pattern mining and linear regression analyses independently identified a 3-marker haplotype across intron B to be significantly associated with low postdexamethasone cortisol (P = 0.03). Carriage of this haplotype occurred in 41% of the individuals with low postdexamethasone cortisol versus 23% in the combined other quartiles. The authors concluded that a 3-point haplotype within intron B is associated with enhanced sensitivity to glucocorticoids and that this haplotype may help predetermine variation in clinical response to glucocorticoid therapy and also assist the understanding of diseases related to glucocorticoid production. Van den Akker et al. (2006) studied the effect of the GCCR haplotype characterized by the GR-9-beta polymorphism on GCCR transactivation and transrepression. The 53 persons carrying the GR-9-beta haplotype without ER22/23EK (138040.0011) had no significant differences in their BMI, waist-to-hip ratio, fat spectrum, and insulin sensitivity or in their cortisol response to dexamethasone and levels of C-reactive protein, compared with 113 noncarriers. Ex vivo, GCCR-induced upregulation of GCCR-induced leucine zipper mRNA via transactivation did not significantly differ in GR-9-beta homozygotes, whereas the downregulation of IL2 (147680) expression via transrepression was decreased. Van den Akker et al. (2006) concluded that persons carrying the GR-9-beta haplotype seem to have a decreased GCCR transrepression with normal transactivation. DeRijk et al. (2006) studied the role of a GCCR common polymorphism (I180V) in the neuroendocrine response to a psychosocial stressor and in electrolyte regulation. Carriers of the 180V allele showed higher saliva (P less than 0.01), plasma cortisol (P less than 0.01), and heart rate responses (P less than 0.05) to the Trier Social Stress Test than noncarriers (I180I). In vitro testing of the 180V allele revealed a mild loss of function using cortisol as a ligand, compared with the 180I allele. DeRijk et al. (2006) concluded that cortisol and heart rate responses to a psychosocial stressor are enhanced in carriers of the 180V variant.