EYES2023 ESE Young Endocrinologists and Scientists (EYES) 2023 Oral communication 1: Adrenal Diseases (8 abstracts)
Constitutional duplication of PRKACA gene is a cause of isolated primary pigmented nodular adrenocortical disease (PPNAD): Results of its systematic search in bilateral nodular adrenal disease
Patricia Vaduva 1 , Florian Violon 1 , Gérald Raverot 2 , Stephanie Espiard 3 , Amina Attia 4 , Lucas Bouys 1 , Karine Perlemoine 1 , Albin Chasavang 5 , Sylvie Hieronimus 6 , Marie Christine Vantyghem 3 , Michel Polak 7 , Ragazzon Bruno 8 , Anne Jouinot 1 , Eric Pasmant 5 & Jerome Bertherat 9
1Cochin Institute, Genomic and Signaling of Neuroendocrine Tumors Team, Inserm U1016, Cnrs Umr8104, Paris, France; 2Groupement Hospitalier Est, Inserm U1052, Lyon I University Université de Lyon, Lyon, France; 3Lille University Hospital, Department of Endocrinology, Diabetology, Metabolism and Nutrition, Lille, France; 4Hospital Pitié-Salpêtrière, Thyroid-Endocrine Tumors, Paris, France; 5Cochin Hospital, Department of Oncogenetics, Paris, France; 6Nice University Hospital, Department of Endocrinology, Diabetology and Reproductive Medicine, Nice, France; 7Inserm U1016, Cochin Institute, Université de Paris, Pediatric Endocrinology, Gynecology and Diabetology Unit, Hôpital Universitaire Necker-Enfants Malades, Ap-Hp, Paris, France; 8Inserm U1016, Institut Cochin, Cnrs Umr8104, Endocrinology Metabolism Diabetes Department, Paris, France; 9Hospital Cochin, Endocrinology, Cochin Institute, Inserm U1016, Paris, France.
Background: Constitutional duplications of the PRKACA gene locus have been described as responsible for adrenal Cushing’s disease.
The objective here was to evaluate the results of its systematic screening in bilateral adrenal nodular disease and to specify the associated phenotype.
Methods: Between 2020 and 2023, 440 consecutive index cases with macronodular or micronodular adrenal hyperplasia or Carney Complex (CNC) 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.
Results: Constitutional duplications of PRKACA were identified in 5 index cases and 7 of the 11 screened relatives (sex-ratio =1 male/2 female), supporting the involvement of the PRKACA oncogene through a constitutional copy gain mechanism. The whole genome sequencing performed for 4 index cases did not find any other shared pathogenic variant in another gene involved in human pathology in the duplicated region, nor any other alteration in genes implicated in adrenal pathology. All index cases had Primary Pigmented Nodular Adrenocortical Disease (PPNAD) responsible for Cushing’s syndrome and ACTH-independent hypercorticism, diagnosed at a median of 20 years (min=9; max=32). They were treated by bilateral adrenalectomy. The adrenals were described as normal on conventional imaging in 3/5 cases, but iodocholesterol scintigraphy showed diffuse bilateral hyperfixation. No other manifestation of the Carney complex was observed apart from PPNAD (median follow-up 11 years), except for testicular calcifications in 1/4 patients.
Conclusions: Constitutional duplication of PRKACA is a rare cause of PPNAD. It does not appear to be involved in other forms of adrenal 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 for patients with PPNAD.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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