PRKAR1A mutations in primary pigmented nodular adrenocortical disease

Abstract

Primary Pigmented Nodular Adrenocortical Disease (PPNAD) is a rare primary bilateral adrenal defect causing corticotropin-independent Cushing's syndrome. It occurs mainly in children and young adults. Macroscopic appearance of the adrenals is characteristic with small pigmented micronodules observed in the cortex. PPNAD is most often diagnosed in patients with Carney complex (CNC), but it can also be observed in patients without other manifestations or familial history (isolated PPNAD). The CNC is an autosomal dominant multiple neoplasia syndrome characterized by the association of myxoma, spotty skin pigmentation and endocrine overactivity. One of the putative CNC genes has been identified as the gene of the regulatory R1A subunit of protein kinase A (PRKAR1A), located at 17q22-24. 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. Interestingly, such inactivating germline PRKAR1A mutations have also been found in patients with isolated PPNAD. The hot spot PRKAR1A mutation termed c.709[-7-2]del6 predisposes mostly to isolated PPNAD, and is the first clear genotype/phenotype correlation described for this gene. Somatic inactivating mutations of PRKAR1A have been observed in macronodules of PPNAD and in sporadic cortisol secreting adrenal adenomas. Isolated PPNAD is a genetic heterogenous disease, and recently inactivating mutations of the gene of the phosphodiesterase 11A4 (PDE11A4) located at 2q31-2q35 have been identified in patients without PRKAR1A mutations. Interestingly, both PRKAR1A and PDE11A gene products control the cAMP signaling pathway, which can be altered at various levels in endocrine tumors.

Expression of progesterone and estradiol receptors in normal adrenal cortex, adrenocortical tumors, and primary pigmented nodular adrenocortical disease

“…In these cells, LH via the production of cAMP, but not estradiol, induces PR mRNA expression (Clemens et al 1998). In patients with PPNAD, inactivating mutations of PDE11A4, which encodes a phosphodiesterase, and of PRKAR1A, which encodes the RI subunit of the cAMP-dependent PKA, are frequently identified (Cazabat et al 2006). Somatic mutations of this gene are also observed in a small number of cortisol-secreting ACA, unrelated to CNC.…”

Newly Diagnosed Carney Complex in 3 Young Adults with Primary Adrenal Cushing Syndrome – A Case Series and Review of the Literature

“…CNC is a rare endocrine multi-organ syndrome previously diagnosed in ~750 patients (6). A mutation in the PRKAR1A gene has been identified in more than 70% of the cases, including 80% of those with PPNAD (7,10). PRKAR1A is located at the 17q 24.2-24.3 locus and is composed of 11 exons (6).…”

Psychiatric disorders as predominant symptom of hypercortisolism in 17 year-old girl with primary pigmented nodular adrenocortical disease

“…W połowie przypadków PPNAD jest składową zespołu Carneya, choroby występującej rodzinnie, o autosomalnie dominują-cym dziedziczeniu. Za PPNAD najczęściej odpowiedzialna jest mutacja podjednostki regulatorowej R1 alfa kinazy proteinowej A (PRKAR1A) [11,12].…”