Primary generalized glucocorticoid resistance (PGGR) or Chrousos syndrome is a rare familial or sporadic disorder characterized by partial generalized tissue insensitivity to glucocorticoids with corresponding activation of the hypothalamic-pituitary-adrenal (HPA) axis and hypersecretion of adrenocorticotropic hormone (ACTH).
The prevalence of the condition is not known. The non-specific clinical presentation may result in under-diagnosis or misclassification of cases. To date, approximately 15 cases have been reported.
The clinical features of PGGR include manifestations of mineralocorticoid and/or androgen excess. Arterial hypertension and hypokalemic alkalosis are the characteristics of mineralocorticoid excess. Signs of androgen excess include ambiguous genitalia (in a karyotypic female at birth) and gonadotropin-independent precocious puberty (in children of either gender); acne, hirsutism and hypofertility (in both sexes); male-pattern hair loss, menstrual irregularities and oligo-anovulation in females, and oligospermia in males. The clinical spectrum of PGGR is broad, ranging from most severe to mild forms, while a number of patients may be asymptomatic, displaying biochemical alterations only. Generally, there are no manifestations of glucocorticoid excess. Glucocorticoid deficiency has only been rarely reported and is characterized by hypoglycemic generalized tonic-clonic seizures, excessive fatigability with feeding, susceptibility to infections and concurrent growth hormone deficiency.
The molecular basis of PGGR has been ascribed primarily to mutations in the NR3C1 gene (5q31-q32), which impair the molecular mechanisms of hGR action and decrease tissue sensitivity to glucocorticoids. Patients have generalized, partial, target-tissue insensitivity to glucocorticoids. Through activation of the HPA axis, they have hypersecretion of ACTH, resulting in adrenocortical hyperplasia, increased cortisol secretion, and increased production of adrenal steroids with mineralocorticoid and/or androgenic activity.
The diagnosis is based on the presence of clinical and laboratory signs of alternation in HPA axis activity. It requires complete personal and family history. Changes in CNS function (headaches, visual impairment, seizures), in growth and sexual maturation, and irregular menstrual cycles in females, may be suggestive of PGGR. Increased 24h urinary free cortisol (UFC) excretion in the absence of clinical manifestations of hypercortisolism is diagnostic. Increases in serum cortisol and androgen concentrations are however highly variable. Patients can also be tested with high-dose dexamethasone to confirm resistance of the HPA axis.
The differential diagnosis includes polycystic ovarian syndrome, congenital adrenal hyperplasia, precocious puberty as well as mild Cushing disease (see these terms) and pseudo-Cushing states.
PGGR is a familial or sporadic condition. Autosomal dominant and autosomal recessive patterns of inheritance have been described.
The aim of treatment is to suppress excess secretion of ACTH. Long-term dexamethasone at carefully selected doses on the basis of the clinical manifestations is recommended.
Hypertension and cardiovascular morbidity and mortality may be increased in untreated patients.
Last update: November 2014
- Pr Evangelia CHARMANDARI
- Pr Georges CHROUSOS
- Dr Nicolas NICOLAIDES