Cushing's syndrome and fetal features resurgence in adrenal cortex-specific Prkar1a knockout mice.

Carney complex (CNC) is an inherited neoplasia syndrome with endocrine overactivity. Its most frequent endocrine manifestation is primary pigmented nodular adrenocortical disease (PPNAD), a bilateral adrenocortical hyperplasia causing pituitary-independent Cushing's syndrome. Inactivating mutations in PRKAR1A, a gene encoding the type 1 alpha-regulatory subunit (R1alpha) of the cAMP-dependent protein kinase (PKA) have been found in 80% of CNC patients with Cushing's syndrome. To demonstrate the implication of R1alpha loss in the initiation and development of PPNAD, we generated mice lacking Prkar1a specifically in the adrenal cortex (AdKO). AdKO mice develop pituitary-independent Cushing's syndrome with increased PKA activity. This leads to autonomous steroidogenic genes expression and deregulated adreno-cortical cells differentiation, increased proliferation and resistance to apoptosis. Unexpectedly, R1alpha loss results in improper maintenance and centrifugal expansion of cortisol-producing fetal adrenocortical cells with concomitant regression of adult cortex. Our data provide the first in vivo evidence that loss of R1alpha is sufficient to induce autonomous adrenal hyper-activity and bilateral hyperplasia, both observed in human PPNAD. Furthermore, this model demonstrates that deregulated PKA activity favors the emergence of a new cell population potentially arising from the fetal adrenal, giving new insight into the mechanisms leading to PPNAD.

Corticotropin-releasing hormone production by a small cell carcinoma in a patient with ACTH-dependent Cushing's syndrome.

We describe a patient with Cushing's syndrome and metastatic small cell lung cancer. The plasma ACTH concentrations were markedly elevated (91.6 pmol/L), and the AM cortisol did not suppress by > 50% overnight after administration of 8 mg dexamethasone, both consistent with the ectopic ACTH syndrome. Immunohistochemical studies of a single metastatic tumor specimen, however, demonstrated an absence of ACTH and yet an abundance of corticotropin-releasing hormone (CRH). In addition, radioimmunoassay of the patient's plasma demonstrated persistently elevated CRH concentrations. The majority of the plasma CRH immunoreactivity exhibited the same chromatographic mobility as synthetic r/h CRH (1-41) on HPLC. Failure to evaluate the tumor tissue for the presence of ACTH and/or CRH would have led to the erroneous conclusion that this patient's Cushing's syndrome resulted from paraneoplastic ACTH production. We conclude that immunoassay of plasma for both ACTH and CRH and, perhaps, immunostaining of tumor samples are required to distinguish between the ectopic ACTH and CRH syndromes.