EYES2024 ESE Young Endocrinologists and Scientists (EYES) 2024 Adrenals and Neuroendocrine Tumors (17 abstracts)
Genetic alterations guide the phenotype of patients with PBMAH: study of 354 index cases
Patricia Vaduva 1 , Lucas Bouys 1,2 , Anne Jouinot 1 , Anna Vaczlavik 2 , Helaine Charchar 3 , Stephanie Espiard 4 , Peter Kamenicky 5 , Marie-Christine Vantyghem 4 , Martin Fassnacht 6 , Rossella Libé 2 , Guillaume Assié 1,2 , Antoine Tabarin 7 , Gerald Raverot 8 & Maria Fragoso 3
1Genomic and signaling of neuroendocrine tumors team, INSERM U1016, CNRS UMR8104, Cochin Institute, Paris Cité University, 75005 Paris, France; 2Department of Endocrinology, Reference Center for Rare Adrenal Diseases, Cochin Hospital, APHP, 75014 Paris, France; 3Department of Endocrinology, Adrenal Unit, University of Sao Paulo, Sao Paulo, Brazil; 4Department of Endocrinology, Diabetology, Metabolism and Nutrition, Lille University Hospital, 59000 Lille, France; 5Paris Saclay University, Department of Endocrinology and Reproduction, Reference center for rare pituitary diseases, Bicêtre Hospital, APHP, Paris, France; 6Division of Endocrinology and Diabetes, Department of internal medicine, University Hospital of Wurzburg, Wurzburg, Germany; 7Department of Endocrinology, Diabetology, Metabolism and Nutrition, Haut Lévêque Hospital, Bordeaux University Hospital, Bordeaux, France; 8Department of Endocrinology, Groupement Hospitalier Est, Hospices Civils de Lyon, 69677 Bron, France; 9EDIMO & Human Genetics and Precision Medicine, Institute for Molecular Biology & Biotechnology (IMBB), Foundation for Research & Technology Hellas (FORTH), Heraklion, Greece
Objective: Primary bilateral macronodular adrenal hyperplasia (PBMAH) is the most common cause of Cushing’s syndrome with bilateral adrenal origin. Pathogenic variants of ARMC5 and KDM1A tumor suppressor genes are causing around 25% of isolated PBMAH cases and variants of PDE11A gene, are frequently associated with the disease, but causality has not been formally established.
Methods: The leukocyte DNA of 354 index cases of PBMAH, from 8 European, American and Brazilian centers, was sequenced for these 3 genes and the phenotype of the patients was analyzed.
Results: In this cohort, 19.2% of patients presented ARMC5 and 2.1% KDM1A pathogenic variants (mutually exclusive) Patients had PDE11A pathogenic variants in 11.4% of cases (similarly distributed in ARMC5-altered and wild-type group). Patients carrying pathogenic variants of ARMC5 and KDM1A presented a severe phenotype, compared to wild-type patients, with a significant increase in urinary free cortisol (UFC) (2.18 and 2.86 vs 0.95 ULN (upper limit of normal), P= 0.004) and midnight cortisol (338.9 and 432.85 vs 188.97 nmol/l, P = 0.004) as well as more adrenal nodules (10.82 and 6.67 vs 3.45, P = 5.94 -7). Patients with pathogenic variants of PDE11A had a phenotype of attenuated severity with lower UFC (0.7 vs 1.25 ULN, P = 0.0002), midnight cortisol (157.81 vs 222.19 nmol/l, P = 0.016) and number of adrenal nodules (3.46 vs 4.74, P = 0.048) than wild-type PDE11A individuals, conferring a phenotypic modulatory role to this gene. Thus, adrenalectomy was performed in 71%, 60% and 37% of patients with pathogenic variants of KDM1A, ARMC5 and PDE11A, respectively. In this cohort, 44 patients (12.5%) underwent bilateral adrenalectomy and 64 patients (18%) unilateral adrenalectomy as a first line treatment, with 13 patients having secondarily a totalization, after unilateral adrenalectomy, because of inefficiency.
Discussion: The strong genotype/phenotype correlation observed in PBMAH encourages monitoring and treatment based on the genetic alterations of patients.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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