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Cushing syndrome

Orpha number ORPHA553
Synonym(s) Cushing's syndrome
Hyperadrenocorticism
Hypercortisolism
Prevalence 1-9 / 100 000
Inheritance Autosomal dominant
Not applicable
Age of onset All ages
ICD-10
  • E24.0
  • E24.1
  • E24.2
  • E24.3
  • E24.4
  • E24.8
  • E24.9
ICD-O -
OMIM -
UMLS
  • C0001622
  • C0010481
MeSH
  • D000308
  • D003480
MedDRA
  • 10011652
  • 10020562
  • 10020564
  • 10020610
SNOMED CT
  • 275437005
  • 47270006

Summary

Cushing's syndrome (CS) encompasses a group of hormonal disorders caused by prolonged and high exposure levels to glucocorticoids that can be of either endogenous (adrenal cortex production) or exogenous (iatrogenic) origin.

Prevalence of endogenous CS is 1/26,000 and, in the EU, it has an annual incidence of 1/1,400,000-1/400,000, with a peak incidence at 25-40 years of age.

Typical clinical features are truncal and facial obesity, signs of hypercatabolism (thinned skin, purple striae, ecchymosis, bruising with no obvious trauma, proximal muscle weakness with amyotrophy, unexplained osteoporosis) and, in children, weight gain with decreasing growth velocity. Other less specific features include fatigue, high blood pressure, glucose intolerance, hypokalemia, acne, hirsutism, menstrual irregularity, diminished libido, erectile dysfunction, and neuropsychological disturbances (including depression, emotional irritability, sleep disturbances, cognitive deficits, increased susceptibility to infections, urolithiasis). Mild CS (termed subclinical or occult) is more common than previously thought and has been identified while investigating for diabetes, osteoporosis, hypertension or neuropsychological disturbances.

Exogenous CS is due to anti-inflammatory steroid medications, ritonavir co-administration in HIV-infected patients or high-dose megestrol. Endogenous CS includes adrenocorticotropic hormone (ACTH) dependent CS (75-80%) and ACTH-independent CS (20-25%). ACTH-dependent CS is due to pituitary adenomas (80%) or to ectopic ACTH secretion (20%). ACTH-independent CS is due to unilateral adrenocortical tumors, either benign (adrenocortical adenoma: 60%) or malignant (adrenocortical carcinoma: 40%) or to bilateral adrenocortical hyperplasia, including ACTH-independent macronodular adrenal hyperplasia (AIMAH) and primary pigmented nodular adrenocortical disease (PPNAD) (see these terms). CS may occur in rare genetic conditions such as multiple endocrine neoplasia type 1 (MEN 1), Carney complex (CNC), McCune-Albright syndrome (MAS), Li-Fraumeni syndrome (LFS) (see these terms) and familial isolated pituitary adenoma (FIPA).

Diagnosis of a hypercortisolemic state is based on recommended 1st line tests (at least two measurements of 24h urinary cortisol and late night salivary cortisol, and 1 mg overnight or 48h-2 mg dexamethasone suppression test) and 2nd line tests that should be performed by an endocrinologist (either one of the above or, in some cases, midnight serum cortisol measurement, serum cortisol cycle, dexamethasone-suppressed corticotropin-releasing hormone (Dex-CRH) test, desmopressin test or even CRH-test). Abnormal results should lead to testing for the cause of CS. Normal 1st line tests should be repeated in patients with suspected cyclic hypercortisolism, or who show additional signs over time. After excluding exogenous CS, the differential diagnosis includes pseudo-CS that regresses after resolution of the cause (alcoholism and depression). Suspicion of a genetic condition warrants a specialized multidisciplinary genetic consultation.

Antenatal or preimplantation diagnosis may be proposed in families with identified mutations and severe/incurable diseases (e.g. Li-Fraumeni syndrome).

Genetic counseling may be proposed in families with a known disease causing mutation.

Management, with a multidisciplinary strategy, depends on the cause and impact of CS and any comorbidities. It may include pituitary or adrenal surgery, medical treatment (o,p'DDD, ketoconazole, metyrapone), and radiotherapy. With some treatment plans, temporary or permanent replacement therapy is imperative. Any complications should be managed.

Prognosis depends on the cause of CS and severity of associated complications. In the majority of cases, CS can be treated effectively.

Expert reviewer(s)

  • Pr Jérôme BERTHERAT
  • Dr Laurence GUIGNAT

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Detailed information

Clinical practice guidelines
  • FR (2008,pdf)
  • ES (2010,pdf)
  • DE (2010)
Article for general public
  • FR (2006,pdf)
  • ES (2011,pdf)
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