European journal of endocrinology · 2025
PRKACA constitutional duplication: a specific cause of primary pigmented nodular adrenocortical disease.
СтатьяНазвание и аннотация: Перевод в очереди
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Vaduva Patricia, Violon Florian, Chansavang Albain, Hadjadj Djihad, Raverot Gerald, Espiard Stéphanie, Attia Amina, Bouys Lucas, Thomeret Louis, Weber Kuhn Aliny, Perlemoine Karine, Chevalier Nicolas, Vantyghem Marie-Christine, Polak Michel, Fragoso Maria, Berthon Annabel, Ragazzon Bruno, Sibony Mathilde, Pasmant Eric, Jouinot Anne, Bertherat Jérôme
Аннотация
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.
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.