Cushing Disease

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Retrieved

2021-01-23

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Orphanet

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Drugs

2S,4R ketoconazole, Ketoconazole ( KETOCONAZOLE HRA, NIZORAL ), Mifepristone ( KORLYM )

2S,4R ketoconazole, Ketoconazole ( KETOCONAZOLE HRA, NIZORAL ), Mifepristone ( KORLYM ), Osilodrostat ( ISTURISA ), Pasireotide ( SIGNIFOR, SIGNIFOR LAR ), Relacorilant, Synthetic double-stranded short interfering RNA oligonucleotide directed against proopiomelanocortin

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Cushing disease (CD) is the most common cause of endogenous Cushing syndrome (CS; see this term) and is due to pituitary chronic over-secretion of ACTH by a pituitary corticotroph adenoma.

Epidemiology

Exact prevalence is unknown. Prevalence of endogenous CS is estimated at around 1/26,000, with CD representing more than two-thirds of all cases. Recent data suggests that mild CD is more common than previously thought.

Clinical description

The female-to-male ratio of CD is 4-5:1, except in prepubertal patients, in which a strong male predominance is observed. The peak incidence is at 25-40 years of age. The disease manifests with signs of CS (truncal and facial obesity and signs of hypercatabolism) as well as skin hyperpigmentation and/or neurological complications in some cases of corticotroph macro-adenoma.

Etiology

Little is known about the underlying pathogenesis of pituitary tumors. Most pituitary adenomas arise in a sporadic setting with rare cases (< 5 %) developing as part of familial syndromes such as multiple endocrine neoplasia type 1 (MEN 1), which is caused by mutations in the MEN1 gene (11q13), familial isolated pituitary adenomas (FIPA), in which mutations of the AIP gene ( 11q13-32) have been found in 15% of patients, and the recently described multiple endocrine neoplasia type 4 (MEN 4) which is caused by mutations in the CDKN1B gene (see these terms).

Diagnostic methods

The first diagnostic step is to confirm CS (i.e. hypercortisolemic state) based on 1st line recommended tests (at least two measurements of 24h urinary cortisol and late night salivary cortisol, and 1 mg overnight or 48-h-2 mg dexamethasone suppression test) and 2nd line tests (either one of the above or midnight serum cortisol measurement or serum cortisol cycle or dynamic tests). The second step of diagnosis is plasma ACTH detection to distinguish ACTH-dependent CS (values greater than 15-20 pg/mL) from ACTH-independent CS (see this term). When in doubt, a 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 syndrome, EASS; see this term). Diagnosis of CD is based on dynamic hormonal tests to analyse the corticotropic response that distinguishes CD (with response often partially regulated: ''positive'' tests) from EASS (with response generally unregulated: ''negative'' tests) as well as measures of tumour markers, imaging (pituitary magnetic resonance imaging (MRI), thoraco-abdomino-pelvic CT, somatostatin receptor scintigraphy) and bilateral inferior petrosal sinus sampling for ACTH assay.

Differential diagnosis

The differential diagnoses of CD are the causes of CS (see this term).

Genetic counseling

Suspicion of a genetic condition warrants a specialized multidisciplinary genetic consultation.

Management and treatment

Removal of the tumor may lead to full recovery but there is a 15-25 % recurrence risk and a 20-30% persistence risk after surgery. Transsphenoidal pituitary surgery is the first-line treatment for accessible and non-invasive pituitary microadenoma, and in some cases of negative MRI, if CD is confirmed by inferior petrosal sinus sampling. After successful pituitary surgery, hydrocortisone replacement is often required. When surgery fails, reintervention may be proposed. If pituitary surgery is not possible or unsuccessful, alternative options should be considered individually such as medical treatment, bilateral adrenalectomy or pituitary radiotherapy.

Prognosis

Untreated CD can be life-threatening.