From the First Case Reports to KDM1A Identification: 35 Years
                    of Food (GIP)-Dependent Cushing’s Syndrome

Lucas Bouys; Jérôme Bertherat

doi:10.1055/a-2359-8051

Experimental and Clinical Endocrinology & Diabetes, Inhaltsverzeichnis

Exp Clin Endocrinol Diabetes 2024; 132(12): 697-704
DOI: 10.1055/a-2359-8051

Review

From the First Case Reports to KDM1A Identification: 35 Years of Food (GIP)-Dependent Cushing’s Syndrome

Lucas Bouys

¹Department of Endocrinology and National Reference Center for Rare Adrenal Diseases, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, 27 rue du Faubourg Saint-Jacques, F-75014, Paris, France

²Genomics and Signaling of Endocrine Tumors, Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris-Cité

,

Jérôme Bertherat

¹Department of Endocrinology and National Reference Center for Rare Adrenal Diseases, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, 27 rue du Faubourg Saint-Jacques, F-75014, Paris, France

²Genomics and Signaling of Endocrine Tumors, Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris-Cité

› Institutsangaben

Abstract

Food-dependent Cushing’s syndrome (FDCS) is a rare presentation of hypercortisolism from adrenal origin, mostly observed in primary bilateral macronodular adrenal hyperplasia (PBMAH) but also in some cases of unilateral adrenocortical adenoma. FDCS is mediated by the aberrant expression of glucose-dependent insulinotropic peptide (GIP) receptor (GIPR) in adrenocortical cells. GIP, secreted by duodenal K cells after food intake, binds to its ectopic adrenal receptor, and stimulates cortisol synthesis following meals. FDCS was first described more than 35 years ago, and its genetic cause in PBMAH has been recently elucidated: KDM1A inactivation by germline heterozygous pathogenic variants is constantly associated with a loss-of-heterozygosity of the short arm of chromosome 1, containing the KDM1A locus. This causes biallelic inactivation of KDM1A, resulting in the GIPR overexpression in the adrenal cortex. These new insights allow us to propose the KDM1A genetic screening to all PBMAH patients with signs of FDCS (low fasting cortisol that increases after a mixed meal or oral glucose load) and to all first-degree relatives of KDM1A variant carriers. Given that KDM1A is a tumor suppressor gene that has also been associated with monoclonal gammopathy of uncertain significance and multiple myeloma, the investigation of FDCS in the diagnostic management of patients with PBMAH and further genetic testing and screening for malignancies should be encouraged.

Keywords

PBMAH - adrenal - cushing’s syndrome - food-dependent - GIP-dependent - GIP - GIPR - KDM1A

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