Endogenous Cushing’s syndrome is usually sporadic and divided into ACTH- dependent, and ACTH- independent causes (Table 1). Overall, ACTH- dependent causes account for approximately 80% of cases, and of these 80% are due to corticotroph pituitary adenomas (Cushing’s disease) with an excess female predominance, and the remaining 20% due to the ectopic ACTH syndrome with male predominance. Cushing’s disease, the ectopic ACTH syn drome, and adrenal adenomas may also be found in the context of multiple endocrine neoplasia 1 (MEN 1).
Table1. Aetiology of Cushing’s syndrome
cushing’s Disease
Most cases of Cushing’s disease are due to corticotroph micro adenomas, a few millimetres in diameter, only being larger than 1 cm (macroadenoma) in 6% of cases. These tumours express the proopiomelanocortin gene (POMC 176830), the pep tide product of which is subsequently cleaved to ACTH. POMC- processing is usually efficient in corticotroph microadenomas, but less so in macroadenomas, which may secrete relatively large amounts of unprocessed POMC. Some pituitary macroadenomas are ‘silent corticotroph adenomas’, and may present with tumour mass effects (e.g. optic chiasm compression) alone; on follow- up, initial absence of cushingoid features may progress to overt clinical Cushing’s syndrome. Approximately 90% of tumours express the corticotropin- releasing hormone (CRH)- 1 receptor, as evidenced by the release of ACTH in response to exogenously administered CRH. Tumours also express the vasopressin- 3 receptor, and respond to vasopressin and desmopressin.
Tumours causing Cushing’s disease are relatively resistant to the effects of glucocorticoids, but POMC expression and ACTH secretion are reduced by higher doses of dexamethasone in 80% of cases. This may be caused by ‘miss- expression’ of the ‘bridging protein’ Brg1 (which is important for glucocorticoid inhibitory feedback on POMC expression) found in corticotroph tumours, and may be one event determining tumourigenesis. Corticotroph tumours also show overexpression of cyclin E, low expression of the cyclin- dependent inhibitor, p27, and a high Ki- 67 expression, all indicative of a relatively high proliferative activity. The excess number of reproductive- aged women with Cushing’s disease, and the fact that there is a male preponderance in prepubertal cases suggest a potential aetiological role for oestrogens. Recent data has emphasized the role of epidermal growth factor (EGF) and its receptor (EGFR), which increases POMC mRNA transcription, cell proliferation and ACTH secretion. Usually, EGFR is degraded by ubiquitination, but somatic missense mutations in ubiquitin- specific protease 8 (USP8), present in approximately 40% of patients with Cushing’s disease, inhibits deubiquitinating activity and so EGFR is re- cycled and signalling is enhanced. Antagonists of EGFR may have therapeutic potential in Cushing’s disease.
ectopic ACTH Secretion
Well differentiated neuroendocrine tumours from any source may cause the ectopic ACTH syndrome, and show a molecular phenotype close to that of pituitary corticotroph tumours. In contrast, data in small cell lung cancer cells have shown that POMC is activated by transcription factors distinct from those in the pituitary, including E2F factors, which are able to bind the promoter when it is in an unmethylated state, suggesting a different pathogenesis.
Adrenal Disease
Approximately 50% of adrenal adenomas causing overt Cushing syndrome exhibit hotspot mutations at L205R of PRKACA, which encodes the catalytic subunit of cAMP- dependent protein kinase A (PKA), and drives cortisol secretion.
In primary bilateral macronodular adrenal hyperplasia (PBMAH), previously also termed AIMAH (for ACTH- independent macronodular hyperplasia), excess cortisol secretion may be associated with either ectopically- expressed receptors or increased eutopic receptor expression, and activation by ligands not usually associated with adrenal steroidogenesis: gastric inhibitory peptide (food- dependent Cushing’s); vasopressin; interleukin- 1; luteinizing hormone; and serotonin. Activation of receptors increasing intracellular cAMP is thought to cause hyperplasia over many years, and hence Cushing’s syndrome. Recently, it has been demonstrated that steroidogenic cell clusters in PBMAH adrenals produce corticotropin, which stimulates cortisol production by the adrenal in an intracrine/ paracrine fashion. Therefore, in PBMAH, cortisol excess seems to mediated by ACTH, albeit of adrenal rather than pituitary or extra- adrenal ectopic origin; therefore, PBMAH is not truly ACTH- independent. For this reason, the term PBMAH is now preferred over AIMAH. The nodules can vary in size and may be massive. Germline inactivating mutations of Armadillo repeat 5 (ARMC5) have now been identified as a common cause of PBMAH. ARMC5 is a cytosolic protein and little is known about its function; in rodent models a more com plex phenotype ensued including compromised T- cell proliferation and differentiation; in humans, ARMC5 has also been reported to be associated with an increased incidence of meningioma alongside Cushing’s syndrome. Characteristically, ARMC5 causes a mild Cushing’s phenotype with onset over years and decades, often resulting in misdiagnosis as metabolic syndrome; family screening can reveal cases much earlier.
Primary pigmented nodular adrenal disease (PPNAD) causes small ACTH- secreting nodules on the adrenal, often not visualized on imaging. PPNAD can be sporadic or part of the Carney’s com plex and most cases occur in late childhood or in young adults, often with a mild or cyclical presentation. Germ line mutations of the regulatory subunit R1A of PKA (PRKAR1A) are present in ap proximately 45% of patients with Carney’s complex and as well as in sporadic PPNAD. Another causative gene locus maps to chromosome 2p16. Interestingly, these patients show a paradoxical increase in cortisol secretion in response to dexamethasone.
McCune– Albright syndrome is due to a postzygotic activating mutation in the GNAS1 gene. The resulting tissue mosaicism results in a varied phenotype, and the disease may present in the first few weeks of life. These mutations lead to constitutive steroidogenesis in the affected adrenal nodules. Mutations of GNAS1 have also been found in cases of PBMAH.
