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.

Abstract

Introduction: 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.

Methods: 301 consecutive PBMAH index cases from 8 international Endocrinology departments were included. Clinical, biological and imaging data were collected retrospectively.

Results: 10 (3.3%) patients carried a germline KDM1A pathogenic or likely pathogenic variant, 60 (19.9%) carried a germline ARMC5 alteration, 231 (76.8%) had no identified genetic predisposition. FDCS was present in all patients with KDM1A variants and absent in the 2 other groups. KDM1A patients had a higher 24h urinary free cortisol (3.0-fold ULN vs 1.36 for ARMC5 patients and 0.66 for wild-type patients, respectively, p=0.0001). 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=0.0003) and a higher midnight plasma cortisol (487 nmol/L vs 297 and 171.96, respectively, p=0.0004). 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=0.0337).

Conclusion: KDM1A germline pathogenic variants are rare in PBMAH and account for less than 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.