PRKACA constitutional duplication was identified in 8 of 781 index cases with bilateral nodular adrenocortical disease, all of whom presented with primary pigmented nodular adrenocortical disease.
Observational (n=781)
What is the phenotype and prevalence of PRKACA constitutional duplications in patients with bilateral nodular adrenocortical disease?
PRKACA constitutional duplications specifically cause primary pigmented nodular adrenocortical disease (PPNAD) and should be screened for in the absence of pathogenic PRKAR1A variants.
OBJECTIVE: Constitutional duplications of PRKACA (PRKACAdup) have been described in rare cases of bilateral nodular adrenocortical disease (BNAD). The aim here was to clarify the phenotype in case of PRKACAdup, through systematic screening in BNAD patients, and study the molecular mechanisms involved. METHODS: Between 2020 and 2024, 781 index cases (IC) with BNAD (693 bilateral macronodular hyperplasia and 88 primary pigmented nodular adrenocortical diseases PPNAD) were genotyped using next-generation sequencing with a panel targeting ARMC5, KDM1A, MEN1, PRKAR1A, PRKACA, or whole-genome sequencing (WGS). Chromatin conformation analyses were performed with Hi-C libraries generated from 3 tumors. RESULTS: PRKACAdup was identified in 8/781 IC and 8/12 screened relatives. WGS performed on 4 IC presenting with PPNAD revealed no other genetic alterations in genes associated with human pathology within the duplicated region, nor any other alterations related to adrenal pathology. All IC with PRKACAdup underwent adrenalectomy for ACTH-independent hypercortisolism, with pathology confirming PPNAD. Other manifestations of Carney complex were observed in 8 of the 16 patients with PRKACAdup, limited to lentiginosis and benign tumors of the gonads. Immunohistochemistry using PRKACA/PRKAR1A antibodies facilitated the differentiation of the responsible genetic alteration. PRKACAdup was found to generate topologically associated neo-domains, in tumor Hi-C maps, as compared to controls. CONCLUSIONS: PRKACAdup causes PPNAD but no other forms of BNAD, so these should be sought in the absence of pathogenic PRKAR1A variants.
Vaduva et al. (Wed,) conducted a observational in Bilateral nodular adrenocortical disease (BNAD) (n=781). PRKACA constitutional duplication (PRKACAdup) was evaluated on Identification of PRKACAdup and associated phenotype. PRKACA constitutional duplication was identified in 8 of 781 index cases with bilateral nodular adrenocortical disease, all of whom presented with primary pigmented nodular adrenocortical disease.