We examined whether this relative hypercortisolism is associated with alterations in the pituitary-adrenocortical response to evening corticotropin-releasing hormone (CRH) stimulation.
Primary macronodular adrenal hyperplasia (PMAH), also known in the past as bilateral macronodular adrenalhyperplasia or adrenocorticotropin (ACTH)-independent macronodular adrenal hyperplasia, is a rare type of Cushing's syndrome (CS) and is associated with bilateralenlargement of the adrenal glands.
A rare case of familial Cushing's syndrome with a common presentation of weight gain due to a mutation of the PRKAR1A gene causing isolated primary pigmented nodular adrenocortical disease.
Heterozygous inactivating mutations of PRKAR1A have been reported initially in about 45% of the CNC index cases and could be found in about 80% of the CNC families presenting mainly with Cushing's syndrome.
The cyclic AMP-dependent PKA catalytic subunit alpha (PRKACA) hotspot point mutation (c.617A > C [p.Leu206Arg]), leading to an increase of basal PKA activity, and formation of cortisol-producing adenoma has been frequently shown to cause the most common form of adrenocorticotropic hormone-independent Cushing 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.
Cushing's disease results from corticotroph adenomas of the pituitary that hypersecrete adrenocorticotropin (ACTH), leading to excess glucocorticoid and hypercortisolism.
Germline heterozygous inactivating mutations of PRKAR1A have been reported in about 45% of patients with CNC, and up to 80% of CNC patients with Cushing's syndrome due to PPNAD.
One of the putative CNC genes located on 17q22-24, (PRKAR1A), has been identified to encode the regulatory subunit (R1A) of protein kinase A. Heterozygous inactivating mutations of PRKAR1A were reported initially in 45 to 65% of CNC index cases, and may be present in about 80% of the CNC families presenting mainly with Cushing's syndrome.
It is uncertain whether thymic neuroendocrine tumors (NET) associated with Cushing's syndrome (CS) produce corticotropin-releasing hormone (CRH) and adrenocorticotropin hormone (ACTH) and whether the thymus contains ACTH and/or CRH cells that could originate NET.
Cushing's syndrome due to primary pigmented nodular adrenocortical disease (PPNAD) has been observed in Carney complex patients presenting inactivating germline PRKAR1A mutations.
Cushing's syndrome due to primary pigmented nodular adrenocortical disease have been observed in patients with germline PRKAR1A inactivating mutations.
In this report, we review CNC, its clinical features, diagnosis, treatment and molecular etiology, including PRKAR1A mutations and the newest on PRKACA and PRKACB defects especially as they pertain to adrenal tumors and Cushing's syndrome.
PRKAR1A mutation analysis in two large families with CS and no other CNC manifestations demonstrated a M1V germline mutation; a total of 21 asymptomatic individuals were screened, and mutation carriers were evaluated for CNC.
Genetic testing of the 2 sisters and their mother (who also had multiple facial lentigines but did not have Cushing syndrome) revealed a novel mutation in the PRKAR1A gene.
Genomics studies have identified a key mutation (L205R) in the α-isoform of the catalytic subunit of cAMP-dependent protein kinase (PKACα) in adrenal adenomas of patients with adrenocorticotropic hormone-independent Cushing's syndrome.
A base substitution (c.439A>G/p.S147G) in PRKAR1A was identified in the proposita, in the three others with PPNAD, in the proposita's twin daughters who had lentigines but no evidence of hypercortisolism, and in five other family members, including one without lentigines or evidence of hypercortisolism.
Hypersecretion of adrenocorticotropin hormone (ACTH), the key activator of the cAMP pathway in adrenal cortex, is associated with adrenocortical hyperplasia and cortisol oversecretion (Cushing's syndrome).