Results of systematic KDM1A genotyping in a large series of Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) patients and analysis of the genotype/phenotype correlation

Lucas Bouys; Anna Vaczlavik; Patricia Vaduva; Anne Jouinot; Florian Violon; Annabel Berthon; Peter Kamenicky; Fanny Chasseloup; Stephanie Espiard; Marie-Christine Vantyghem; Antoine Tabarin; Magalie Haissaguerre; Gerald Raverot; Francoise Borson-Chazot; Villares Fragoso Maria Candida Barisson; Charchar Helaine; Martin Reincke; Kroiss Matthias; Constantine A. Stratakis; Crystal Kamilaris; Karine Perlemoine; Lionel Groussin; Igor Tauveron; Maxime Barat; Laurence Guignat; Guillaume Assie; Eric Pasmant; Bruno Ragazzon; Jerome Bertherat

doi:10.1530/endoabs.99.OC11.5

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Endocrine Abstracts (2024) 99 OC11.5 | DOI: 10.1530/endoabs.99.OC11.5

ECE2024 Oral Communications Oral Communications 11: Adrenal and Cardiovascular Endocrinology | Part II (6 abstracts)

Results of systematic KDM1A genotyping in a large series of Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) patients and analysis of the genotype/phenotype correlation

Lucas Bouys ^1,2 , Anna Vaczlavik ¹ , Patricia Vaduva ² , Anne Jouinot ² , Florian Violon ² , Annabel Berthon ² , Peter Kamenicky ³ , Fanny Chasseloup ³ , Stéphanie Espiard ⁴ , Marie-Christine Vantyghem ⁴ , Antoine Tabarin ⁵ , Magalie Haissaguerre ⁵ , Gerald Raverot ⁶ , Francoise Borson-Chazot ⁶ , Maria Candida Barisson Villares Fragoso ⁷ , Charchar Helaine ⁷ , Martin Reincke ⁸ , Kroiss Matthias ⁸ , Constantine A. Stratakis ⁹ , Crystal Kamilaris ⁹ , Karine Perlemoine ² , Lionel Groussin , Igor Tauveron ¹⁰ , Maxime Barat ¹ , Laurence Guignat ¹ , Guillaume Assié ¹ , Eric Pasmant ¹ , Bruno Ragazzon ² & Jerome Bertherat ¹

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Author affiliations

¹Cochin Hospital, Paris, France; ²Cochin Institute, Paris, France; ³Bicetre Hospital, Le Kremlin-Bicêtre, France; ⁴Hospital Center University De Lille, Lille, France; ⁵Hospital Center University De Bordeaux, Bordeaux, France; ⁶Hospices Civils de Lyon-HCL, Lyon, France; ⁷University of São Paulo, Brazil; ⁸Klinikum der Universität München, München, Germany; ⁹Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, United States; ¹⁰CHU Gabriel-Montpied, Clermont-Ferrand, France

Introduction: Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) is a rare disease responsible for variable levels of cortisol excess. Constitutional pathogenic variants of the tumor suppressor gene ARMC5 are its most frequent molecular cause (20% of index cases). Recently, KDM1A has been identified as the causing gene for PBMAH associated with food-dependent Cushing’s syndrome (FDCS), consecutive to the illegitimate expression of the GIP receptor (GIPR) in adrenocortical nodules. KDM1A has also been associated with multiple myeloma. This work aimed to assess the prevalence of KDM1A mutations in a large series of PBMAH index cases.

Methods: The constitutional genotyping of KDM1A and ARMC5 genes has been performed by targeted NGS in 301 PBMAH index cases (67% female) from 8 centers (Cochin, Bicêtre, Lille, Lyon, Bordeaux, Sao Paulo, NIH, Munich), presenting with bilateral adrenal nodules and evidence for autonomous cortisol secretion (plasma cortisol after 1 mg dexamethasone suppression test >50 nmol/l and/or elevated 24 h urinary cortisol and/or high midnight plasma cortisol and/or suppressed plasma ACTH).

Results: Among the 301 index cases, 10 (3.3%) had a KDM1A and 60 (19.9%) an ARMC5 pathogenic or likely pathogenic constitutional variant. KDM1A patients are all women with FDCS. Their median 24 h cortisoluria was 3.0N (0.7-6.6) vs 1.23N in ARMC5 patients (0.2-10.7) and 0.66N in wild-type patients (0.1-10.1), P<0.001. Morning plasma cortisol was significantly lower: 192 nmol/l (86-672) vs 407 (111-1166) vs 428 (170-859), respectively, P<0.001; and their midnight cortisol significantly higher: 487 nmol/l (275-634) vs 262 (64-1178) vs 173 (39-867), respectively, P<0.001. A morning/midnight cortisol ratio<0.7 holds a sensitivity of 100% and a specificity of 99% for detecting of FDCS in PBMAH. Of the ten KDM1A patients, one had a monoclonal gammopathy of unknown significance (MGUS) and one had a familial history of multiple myeloma.

Conclusion: Constitutional KDM1A pathogenic variants are rare, occurring in less than 5% of PBMAH index cases, mutually exclusive with ARMC5 variants, and always associated with FDCS. Conversely, all patients with FDCS were diagnosed with a germline KDM1A pathogenic variant. KDM1A genotyping should be considered in every patients with PBMAH and a morning/midnight cortisol ratio<0.7 and in all first-degree relatives of known KDM1A pathogenic/likely pathogenic variant carriers. Considering the association with myeloma, we suggest a regular screening by serum protein electrophoresis in pathogenic/likely pathogenic variant carriers. Moreover, gender may play a role in the adrenal effect of KDM1A inactivation, since all KDM1A patients identified in this series were female.