PRKAR1A – Primary Pigmented Nodular Adrenocortical Disease

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare form of ACTH-independent Cushing syndrome characterized by bilateral adrenal micronodules, hypercortisolism, hypertension, and adrenal cortical neoplasms (HP:0100641). Germline inactivating variants in the PRKAR1A gene underlie both isolated PPNAD and PPNAD as part of Carney complex, often presenting in childhood or early adulthood.

Genetic analyses across 86 publications have identified PRKAR1A mutations in 132 of 151 unrelated PPNAD probands, including nonsense, frameshift, splice-site, and missense variants leading to haploinsufficiency or altered RIα function (PMID:39006359). The inheritance is autosomal dominant, with variable penetrance and expressivity, and a broad variant spectrum spanning all coding exons and splice junctions.

Segregation studies in multiple families demonstrated co-segregation of PRKAR1A variants with PPNAD in at least 5 additional affected relatives, including carriers of the recurrent c.1A>G (p.Met1Val) change (PMID:19915019). This confirms familial transmission consistent with dominant inheritance.

Functional assays in patient cells and models show that loss or alteration of RIα results in constitutive PKA activation, dysregulated cAMP signaling, augmented MAPK and Wnt pathway activity, and adrenal tumorigenesis (PMID:12424709, PMID:18241045). Both haploinsufficiency and dominant-negative effects of specific expressed mutants contribute to disease pathogenesis.

No credible reports dispute the PRKAR1A–PPNAD association. Low-penetrance splice variants account for variability, but the overall evidence from genetic, segregation, and functional studies is robust.

Key take-home: In young patients with ACTH-independent Cushing syndrome and bilateral adrenal micronodules, PRKAR1A sequencing is essential for diagnosing PPNAD, guiding management, and assessing risk for Carney complex features.

References

• Frontiers in Endocrinology • 2024 • The clinical characteristics and pathogenic variants of primary pigmented nodular adrenocortical disease in 210 patients: a systematic review. PMID:39006359
• American Journal of Human Genetics • 2002 • Molecular analysis of the cyclic AMP-dependent protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene in patients with Carney complex and primary pigmented nodular adrenocortical disease (PPNAD) reveals novel mutations and clues for pathophysiology: augmented PKA signaling is associated with adrenal tumorigenesis in PPNAD. PMID:12424709
• The Journal of Clinical Endocrinology and Metabolism • 2010 • Association of the M1V PRKAR1A mutation with primary pigmented nodular adrenocortical disease in two large families. PMID:19915019
• Human Mutation • 2008 • In vitro functional studies of naturally occurring pathogenic PRKAR1A mutations that are not subject to nonsense-mediated mRNA decay. PMID:18241045

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