Constitutional duplication of PRKACA gene is a cause of isolated primary pigmented nodular adrenocortical disease (PPNAD)

Patricia Vaduva; Florian Violon; Gerald Raverot; Espiard Stephanie; Amina Attia; Lucas Bouys; Karine Perlemoine; Chansavang Albain; Nicolas Chevalier; Christine Vantyghem Marie; Michel Polak; Bruno Ragazzon; Jouinot  Anne; Eric Pasmant; Jerome Bertherat

doi:10.1530/endoabs.99.P221

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Endocrine Abstracts (2024) 99 P221 | DOI: 10.1530/endoabs.99.P221

ECE2024 Poster Presentations Adrenal and Cardiovascular Endocrinology (95 abstracts)

Constitutional duplication of PRKACA gene is a cause of isolated primary pigmented nodular adrenocortical disease (PPNAD)

Patricia Vaduva ¹ , Florian Violon ¹ , Gerald Raverot ² , Espiard Stephanie ³ , Amina Attia ¹ , Lucas Bouys ^1,4 , Karine Perlemoine ¹ , Chansavang Albain ^5,5 , Nicolas Chevalier ⁶ , Vantyghem Marie Christine ³ , Michel Polak ⁷ , Bruno Ragazzon ¹ , Anne Anne Jouinot ¹ , Eric Pasmant ⁵ & Jerome Bertherat ^1,4,4

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¹Cochin Institute, Paris, France; ²Hospices civils de Lyon, Endocrinology, Brons, France; ³Lille University Hospital, Endocrinology, Diabetology, Metabolism and Nutrition, Lille, France; ⁴Cochin Hospital, Endocrinology, Paris, France; ⁵Cochin Hospital, Department of Tumors and Cancers Molecular Medicine, Paris, France; ⁶Nice University Hospital, Department of Endocrinology, Diabetology and Reproductive medicine, Nice, France; ⁷Necker University Hospital, APHP, Department of Pediatric Endocrinology, Gynecology and Diabetology, Paris

Objective: We have described constitutional duplications of the PRKACA gene locus (encoding the catalytic subunit of the Protein Kinase A) in rare cases of bilateral nodular adrenocortical cause of Cushing’s (Beuschlein et al, NEJM 2014). Its frequency in macronodular and micronodular adrenal diseases and the occurrence of others manifestation of Carney complex are not clearly established. This study performs its systematic screening in a large cohort of adrenocortical nodular disease patients and describes its phenotype.

Methods: Between 2020 and 2023, 487 consecutive index cases with bilateral macronodular adrenal hyperplasia (n=442) or Primary Pigmented Nodular Adrenocortical Disease (PPNAD)/Carney Complex (CNC) (n=45) were genotyped with a targeted NGS panel including the exonic and intronic flanking regions of the ARMC5, MEN1, PRKAR1A (CNC) and PRKACA genes. Familial screening was then offered to relatives. Whole genome sequencing was performed when accepted in index cases with PRKACA duplications.

Results: Constitutional duplications of PRKACA were identified in 5 index cases (representing 11% of patients with PPNAD or CNC) and 7 of the 11 screened relatives, supporting the involvement of the PRKACA oncogene through a constitutional copy gain mechanism. Sex ratio was 1 male/2 female. The whole genome sequencing performed for 4 index cases did not find any other gene involved in human disease in the duplicated region, nor any other alteration in genes implicated in adrenal tumors. All index cases had PPNAD responsible for Cushing’s syndrome and ACTH-independent hypercortisolism, diagnosed at a median of 20 years (range: 9–32). The adrenals were described as normal on conventional imaging in 3/5 cases, but iodocholesterol scintigraphy showed diffuse bilateral uptake. They presented with high 24 h Urinary Free Cortisol (UFC) (range: 2.3 - 9.8 × upper limit of normal) and no response to Dexamethasone suppression test. A paradoxical rise in 24 h UFC after Dexamethasone (Liddle’s test) was observed in 3 patients (1 index and 2 relatives). All patients with Cushing syndrome were treated by bilateral adrenalectomy. Almost no significant manifestations of CNC were observed apart from PPNAD (median follow-up of 10 years [5–16]): mainly lentigines and testicular calcifications in one male patient.

Conclusion: Constitutional duplication of PRKACA is a rare cause of PPNAD. It does not appear to be involved in other forms of adrenocortical nodular disease, nor is it frequently associated with other manifestations of CNC. Constitutional duplication of PRKACA should be searched in the absence of a pathogenic PRKAR1A variant in patients with PPNAD.