Anna Vaczlavik1, Lucas Bouys2, Florian Violon3, Gaetan Giannone2, Anne Jouinot4, Roberta Armignacco2, Isadora P Cavalcante2, Annabel Berthon2, Eric Letouzé5, Patricia Vaduva6, Maxime Barat7, Fidéline Bonnet8, Karine Perlemoine2, Christopher Ribes2, Mathilde Sibony3, Marie-Odile North9, Stéphanie Espiard10, Philippe Emy11, Magalie Haissaguerre12, Igor Tauveron13, Laurence Guignat14, Lionel Groussin1, Bertrand Dousset15, Martin Reincke16, Maria C Fragoso17, Constantine A Stratakis18, Eric Pasmant19, Rossella Libé1, Guillaume Assié1, Bruno Ragazzon2, Jérôme Bertherat20. 1. Institut Cochin, Inserm U1016, CNRS UMR8104, Université de Paris, Paris, France; Department of Endocrinology and National Reference Center for Rare Adrenal Disorders, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France. 2. Institut Cochin, Inserm U1016, CNRS UMR8104, Université de Paris, Paris, France. 3. Institut Cochin, Inserm U1016, CNRS UMR8104, Université de Paris, Paris, France; Department of Pathology, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France. 4. Institut Cochin, Inserm U1016, CNRS UMR8104, Université de Paris, Paris, France; Department of Endocrinology and National Reference Center for Rare Adrenal Disorders, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France; Institut Curie, INSERM U900, MINES ParisTech, PSL-Research University, CBIO-Centre for Computational Biology, Paris, France. 5. Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, INSERM, Paris France. 6. Institut Cochin, Inserm U1016, CNRS UMR8104, Université de Paris, Paris, France; Department of Endocrinology, Diabetology and Nutrition, CHU Rennes, Rennes, France. 7. Institut Cochin, Inserm U1016, CNRS UMR8104, Université de Paris, Paris, France; Department of Radiology, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France. 8. Institut Cochin, Inserm U1016, CNRS UMR8104, Université de Paris, Paris, France; Unit of Hormonology, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France. 9. Unit of Oncogenetics, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France. 10. Institut Cochin, Inserm U1016, CNRS UMR8104, Université de Paris, Paris, France; Department of Endocrinology, Diabetology, Metabolism and Nutrition, CHU Lille, Lille, France. 11. Department of Endocrinology, CHR Orleans, Orléans, France. 12. Department of Endocrinology, University of Bordeaux and CHU Bordeaux, Bordeaux, France. 13. Department of Endocrinology, CHU Clermont Ferrand, Clermont-Ferrand, France. 14. Department of Endocrinology and National Reference Center for Rare Adrenal Disorders, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France. 15. Department of Digestive and Endocrine Surgery, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France. 16. Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany. 17. Department of Endocrinology, Adrenal Unit, University of Sao Paulo, Sao Paulo, Brazil. 18. Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, MD. 19. Institut Cochin, Inserm U1016, CNRS UMR8104, Université de Paris, Paris, France; Unit of Oncogenetics, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France. 20. Institut Cochin, Inserm U1016, CNRS UMR8104, Université de Paris, Paris, France; Department of Endocrinology and National Reference Center for Rare Adrenal Disorders, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France. Electronic address: jerome.bertherat@aphp.fr.
Abstract
PURPOSE: This study aimed to investigate the genetic cause of food-dependent Cushing syndrome (FDCS) observed in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) and adrenal ectopic expression of the glucose-dependent insulinotropic polypeptide receptor. Germline ARMC5 alterations have been reported in about 25% of PBMAH index cases but are absent in patients with FDCS. METHODS: A multiomics analysis of PBMAH tissues from 36 patients treated by adrenalectomy was performed (RNA sequencing, single-nucleotide variant array, methylome, miRNome, exome sequencing). RESULTS: The integrative analysis revealed 3 molecular groups with different clinical features, namely G1, comprising 16 patients with ARMC5 inactivating variants; G2, comprising 6 patients with FDCS with glucose-dependent insulinotropic polypeptide receptor ectopic expression; and G3, comprising 14 patients with a less severe phenotype. Exome sequencing revealed germline truncating variants of KDM1A in 5 G2 patients, constantly associated with a somatic loss of the KDM1A wild-type allele on 1p, leading to a loss of KDM1A expression both at messenger RNA and protein levels (P = 1.2 × 10-12 and P < .01, respectively). Subsequently, KDM1A pathogenic variants were identified in 4 of 4 additional index cases with FDCS. CONCLUSION: KDM1A inactivation explains about 90% of FDCS PBMAH. Genetic screening for ARMC5 and KDM1A can now be offered for most PBMAH operated patients and their families, opening the way to earlier diagnosis and improved management.
PURPOSE: This study aimed to investigate the genetic cause of food-dependent Cushing syndrome (FDCS) observed in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) and adrenal ectopic expression of the glucose-dependent insulinotropic polypeptide receptor. Germline ARMC5 alterations have been reported in about 25% of PBMAH index cases but are absent in patients with FDCS. METHODS: A multiomics analysis of PBMAH tissues from 36 patients treated by adrenalectomy was performed (RNA sequencing, single-nucleotide variant array, methylome, miRNome, exome sequencing). RESULTS: The integrative analysis revealed 3 molecular groups with different clinical features, namely G1, comprising 16 patients with ARMC5 inactivating variants; G2, comprising 6 patients with FDCS with glucose-dependent insulinotropic polypeptide receptor ectopic expression; and G3, comprising 14 patients with a less severe phenotype. Exome sequencing revealed germline truncating variants of KDM1A in 5 G2 patients, constantly associated with a somatic loss of the KDM1A wild-type allele on 1p, leading to a loss of KDM1A expression both at messenger RNA and protein levels (P = 1.2 × 10-12 and P < .01, respectively). Subsequently, KDM1A pathogenic variants were identified in 4 of 4 additional index cases with FDCS. CONCLUSION: KDM1A inactivation explains about 90% of FDCS PBMAH. Genetic screening for ARMC5 and KDM1A can now be offered for most PBMAH operated patients and their families, opening the way to earlier diagnosis and improved management.
Authors: Isadora P Cavalcante; Annabel Berthon; Maria C Fragoso; Martin Reincke; Constantine A Stratakis; Bruno Ragazzon; Jérôme Bertherat Journal: Nat Rev Endocrinol Date: 2022-08-03 Impact factor: 47.564