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. 2025 Feb 1;192(2):119-127.
doi: 10.1093/ejendo/lvaf016.

KDM1A genetic alterations, a rare cause of primary bilateral macronodular adrenal hyperplasia, strongly associated with food-dependent Cushing's syndrome: results of its systematic germline screening in 301 index cases and genotype/phenotype correlation

Lucas Bouys  1   2 , Patricia Vaduva  2 , Anne Jouinot  1   2 , Florian Violon  2   3 , Anna Vaczlavik  1 , Maxime Barat  2   4 , Helaine Charchar  5 , Fanny Chasseloup  6   7 , Crystal Kamilaris  8 , Stéphanie Espiard  9 , Magalie Haissaguerre  10 , Gérald Raverot  11 , Matthias Kroiss  12 , Annabel Berthon  2 , Karine Perlemoine  2 , Igor Tauveron  13 , Laurence Guignat  1 , Rossella Libé  1 , Lionel Groussin  1   2 , Guillaume Assié  1   2 , Eric Pasmant  2   14 , Martin Reincke  12 , Françoise Borson-Chazot  11 , Amandine Ferrière  10 , Marie-Christine Vantyghem  9 , Constantine A Stratakis  8   15 , Peter Kamenický  6   7 , Maria Candida Barisson Villares Fragoso  5 , Albain Chansavang  2   14 , Bruno Ragazzon  2 , Jérôme Bertherat  1   2
Affiliations

KDM1A genetic alterations, a rare cause of primary bilateral macronodular adrenal hyperplasia, strongly associated with food-dependent Cushing's syndrome: results of its systematic germline screening in 301 index cases and genotype/phenotype correlation

Lucas Bouys et al. Eur J Endocrinol. .

Abstract

Objective: ARMC5 is the most prevalent gene predisposing to primary bilateral macronodular adrenal hyperplasia (PBMAH), but germline KDM1A variants have been identified in the rare PBMAH associated with food-dependent Cushing's syndrome (FDCS). The purpose of this work was to assess the frequency of KDM1A variants in a large series of PBMAH patients.

Design: A total of 301 consecutive PBMAH index cases from 8 international endocrinology departments were included. Clinical, biological, and imaging data were collected retrospectively.

Results: Ten (3.3%) patients carried a germline KDM1A pathogenic or likely pathogenic variant, 60 (19.9%) carried a germline ARMC5 alteration, and 231 (76.8%) had no identified genetic predisposition. Food-dependent Cushing's syndrome was present in all patients with KDM1A variants and absent in the 2 other groups. KDM1A patients had a higher 24-h urinary free cortisol (3.0-fold upper limit of normal vs 1.36 for ARMC5 patients and 0.66 for wild-type patients, respectively, P = .0001). In accordance with FDCS pathophysiology, patients with KDM1A variants had a lower morning fasting plasma cortisol (192 nmol/L vs 407 and 428, respectively, P = .0003) and a higher midnight plasma cortisol (487 nmol/L vs 297 and 171.96, respectively, P = .0004). Morning/midnight plasma cortisol ratio below 0.65 holds 100% sensitivity and specificity for the detection of FDCS. All patients with KDM1A variants were women, vs 65% of ARMC5 patients and 67% of wild-type patients (P = .0337).

Conclusions: KDM1A germline pathogenic variants are rare in PBMAH and account for <5% of index cases. KDM1A seems constantly associated with FDCS, which can be evoked in front of a morning/midnight plasma cortisol ratio below 0.65.

Keywords: ARMC5; KDM1A; adrenal; primary bilateral macronodular adrenal hyperplasia.

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Conflict of interest statement

Conflict of interest: G.R. and G.A. are associate editors of European Journal of Endocrinology. The other authors have nothing to disclose.