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.

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.