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

Bouys, L; Vaduva, P; Jouinot, A; Violon, F; Vaczlavik, A; Barat, M; Charchar, H; Chasseloup, F; Kamilaris, C; Espiard, S; Haissaguerre, M; Raverot, G; Kroiss, M; Berthon, A; Perlemoine, K; Tauveron, I; Guignat, L; Libé, R; Groussin, L; Assié, G; Pasmant, E; Reincke, M; Borson-Chazot, F; Ferrière, A; Vantyghem, MC; Stratakis, CA; Kamenický, P; Fragoso, MCBV; Chansavang, A; Ragazzon, B; Bertherat, J

doi:10.1093/ejendo/lvaf016

Adrenal disease

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

Eur J EndocrinolPublished 8 Feb 2025Retrospective multicentre cohort study

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Authors' conclusion

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.

Study context

Population: Consecutive primary bilateral macronodular adrenal hyperplasia (PBMAH) index cases from 8 international endocrinology departments
Participants: 301 index cases

Exposure: KDM1A variant carriers vs ARMC5 alteration carriers vs no identified genetic predisposition
KDM1An = 10
ARMC5n = 60
Wild-typen = 231reference
Outcome: Frequency of KDM1A variants in PBMAH patients

Methodological detailssystematic germline screening, consecutive index cases, 8 international endocrinology departments, retrospective data collection

Systematic germline screening
Consecutive index cases
8 international endocrinology departments
Retrospective data collection

Main finding

As reported in the abstract

Frequency of germline genetic alterations

KDM1A3.3%10

ARMC519.9%60

Wild-type76.8%231

Observational data: associations, not effects.

Further findings

24-h UFC — KDM1A vs ARMC5 and Wild-type · higher with KDM1A

P = 0.0001

KDM1A3.0 fold upper limit of normal

ARMC51.36 fold upper limit of normal

Wild-type0.66 fold upper limit of normal

Morning fasting plasma cortisol — KDM1A vs ARMC5 and Wild-type · lower with KDM1A

P = 0.0003

KDM1A192 nmol/L

ARMC5407 nmol/L

Wild-type428 nmol/L

Midnight plasma cortisol — KDM1A vs ARMC5 and Wild-type · higher with KDM1A

P = 0.0004

KDM1A487 nmol/L

ARMC5297 nmol/L

Wild-type171.96 nmol/L

Outcome	KDM1A	ARMC5	Wild-type	P value
Female sexKDM1A vs ARMC5 and Wild-type	All	65%	67%	P = 0.0337

Food-dependent Cushing's syndrome (FDCS)

FDCS present in all KDM1A patients and absent in ARMC5 and wild-type groups

Morning/midnight plasma cortisol ratio below 0.65 for detection of FDCS

Sensitivity: 100%
Specificity: 100%

Original publication

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. Eur J Endocrinol. Published 8 February 2025. doi:10.1093/ejendo/lvaf016

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