Cushing disease (ORPHA:96253)
A form of adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome, an endogenous Cushing syndrome (CS), characterized by chronic over-secretion of adrenocorticotropic hormone (ACTH) due to a pituitary corticotroph adenoma.
Epidemiology
Cushing disease (CD) is the most common form of endogenous CS. The incidence is estimated to range between 1 out of 588,235 to 833,333 individuals per year, with an estimated incidence of CS (all causes considered) ranging between 1 out of 12,658 to 17,544 individuals per year. The mean age at diagnosis is 40 years and there is a significant female predominance.
Clinical description
The disease manifests with signs of CS (resembling corticosteroid side effects, i.e. faciotruncular fat distribution, hypercatabolic syndrome with thinned skin, proximal muscle weakness, oesteoporosis, metabolic syndrome, ...) as well as skin hyperpigmentation and/or neurological complications in rare cases of corticotropic macro-adenoma.
Etiology
Most corticotroph adenomas arise in a sporadic setting, with somatic activating driver variants in USP8 in around half of cases. Somatic variants in other genes such as USP48 and NR3C1 are less frequent. TP53 and ATXR somatic variants may be associated with more aggressive tumors. Germline mutations are rare.
Diagnostic methods
The first diagnostic step is to confirm CS (i.e. hypercortisolemic state) based on recommended tests. The second step of diagnosis is plasma ACTH detection to distinguish ACTH-dependent CS (values greater than 20 pg/mL) (4.4 pmol/L) from adrenal CS (ACTH values lower than 10 pg/mL) (2.2 pmol/L). When in doubt, a corticotropin-releasing hormone (CRH) test or a high-dose dexamethasone suppression test and adrenal gland computed tomography (CT) are recommended. The third step localizes the site of ACTH over-secretion: pituitary (CD) or non-pituitary (ectopic ACTH secretion; or EAS). Diagnosis of CD is based on dynamic hormonal tests (CRH test, desmopressin test, high-dose dexamethasone suppression test) to analyze the corticotropic response that distinguishes CD (with response often partially regulated: "positive" tests) from EAS (with response generally unregulated: "negative" tests) as well as measures of tumor markers, imaging (pituitary magnetic resonance imaging, thoraco-abdomino-pelvic computed tomography, positron emission tomography/computed tomography with Somatostatin analogue +/- 18-F-DOPA or 18-F-fluorodeoxyglucose), and bilateral inferior petrosal sinus sampling for ACTH assay.
Differential diagnosis
The differential diagnoses of CD are the other forms of Cushing syndrome, nonneoplastic hypercortisolism, generalized glucocorticoid resistance syndrome and lipodystrophy syndromes.
Antenatal diagnosis
Antenatal or preimplantation diagnosis may be proposed in families with identified mutations and severe/incurable diseases.
Genetic counseling
Suspicion of a genetic condition warrants a specialized genetic consultation. In second line, in cases presenting < 18 years or familial forms, genome-wide association studies may be discussed. Genetic counseling may be proposed in families with a known disease-causing mutation.
Management and treatment
Transsphenoidal pituitary surgery by an experienced pituitary surgeon is recommended as the first-line therapy. Removal of the tumor may lead to full recovery but there is a 20-30% persistence risk after surgery and a 15-30% long-term recurrence risk among patients in remission after surgery. After successful pituitary surgery, hydrocortisone replacement is often required for a few months or a few years. In patients who underwent a non-curative surgery, who relapsed or for whom surgery was not possible initially, several options should be considered individually such as second or delayed surgery, medical treatment, bilateral adrenalectomy or pituitary radiotherapy.
Prognosis
Untreated CD can be life-threatening. After remission of CD, sequelae may persist, such as cardiovascular comorbidities, cognitive impairment and psychological disorders.

                            Last update: 
                            February 2024


                            - Expert reviewer(s): 
                            Dr Laurence GUIGNAT | Endo-ERN*


                                * European Reference Network