Cushing syndrome due to bilateral macronodular adrenocortical disease (ORPHA:189427)
A rare adrenal Cushing syndrome characterized by bilateral benign adrenal macronodules (>1 cm) that potentially produce autonomously variable levels of cortisol excess. Although in most cases are ACTH-independent, non-suppressed ACTH levels have been described.
Epidemiology
Cushing syndrome due to bilateral macronodular adrenocortical disease (BMAD) is a rare form of endogenous CS, responsible for less than 2% of cases; the actual frequency remains unclear as only some of BMAD patients have an overt CS. Sporadic BMAD predominantly affects women, but the sex ratio is balanced in patients with ARMC5 pathogenic variants while more than 8/10 patients with KDM1A pathogenic variants are women.
Clinical description
Most BMAD cases are identified incidentally during radiological investigation for unrelated conditions. The adrenal glands can be massively enlarged bilaterally with the presence of numerous macronodules; however diffuse adrenal enlargement without nodules has been described. The clinical presentation depends on the extent of excess cortisol, ranging from asymptomatic forms to severe CS. For symptomatic patients, clinical presentation is typically in the fifth decade of life.
Etiology
In isolated BMAD, variants in the ARMC5 gene accounts for more than 80% of the familial forms and about 20-25% of apparently sporadic cases; variants in the KDM1A gene are responsible for BMAD associated with food-dependent CS. A few cases have been reported in association with mosaic variants of GNAS1, a gene which is also responsible for McCune-Albright syndrome (MAS). Genetic mechanisms still remain to be identified in other cases. Rarely, BMAD can be seen in syndromic diseases such as multiple endocrine neoplasia type 1 (MEN1), familial adenomatous polyposis (FAP), or hereditary leiomyomatosis and renal cell cancer (HLRCC).
Diagnostic methods
The first diagnostic step is to confirm CS (i.e. hypercortisolemic state) based on recommended tests. Diagnosis is often difficult because hypercortisolism usually develops slowly over years, may be cyclical and is often associated with subtle CS. Cortisol secretion may be food-dependent with low fasting cortisol concentrations. Hormonal investigations can demonstrate abnormal stimulation of cortisol secretion by various hormones (e.g. GIP, gonadotropin-releasing hormone, aldosterone or androgen secretion). Usually, in BMAD patients with subclinical or overt CS, ACTH is low or sometimes not detectable; however, non-suppressed ACTH levels have also been described. 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 is to show bilateral adrenal nodular enlargement on radiological imaging. Diagnosis can be confirmed by histological examination.
Differential diagnosis
Differential diagnoses include other causes of adrenal CS, and ACTH-dependent CS including pituitary (Cushing disease) or extra-pituitary tumors (ectopic ACTH secretion), other causes of bilateral adrenal masses with no CS (bilateral pheochromocytoma, primary aldosteronism, congenital adrenal hyperplasia, bilateral metastasis of solid cancer, etc.).
Antenatal diagnosis
Antenatal or preimplantation diagnosis may be proposed for those with severe and incurable diseases.
Genetic counseling
Genetic consultation to offer genetic analysis should be proposed to all patients with BMAD. In a second step, genome-wide study may be discussed. Genetic counseling may be proposed in families with a known disease-causing mutation.
Management and treatment
A surgical or medical treatment should be considered for patients with overt CS and in cases of ascertained mild autonomous cortisol secretion in the presence of clinical consequences of possibly related to hypercortisolism (i.e. diabetes, hypertension, bone fragility). For patients with no evidence for hypercortisolism at diagnosis, active surveillance should be proposed.
Prognosis
Untreated CS due to BMAD can be life-threatening. Prognosis after treatment is good but quality of life may be affected. In cases of moderate hypercortisolism, long-term morbidity is due to the increased cardiovascular and metabolic risk factors associated with mild CS.

                            Last update: 
                            February 2024


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


                                * European Reference Network