Primary Unilateral Macronodular Adrenal Hyperplasia With Concomitant Glucocorticoid And Androgen Excess And KDM1A Inactivation

Background: Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing’s syndrome. Individuals with PBMAH and foodGIP-dependent Cushing’s syndrome due to ectopic aberrant expression of the gastric inhibitory polypeptide receptor (GIPR) typically harbour inactivating KDM1A sequence variants. Primary unilateral macronodular adrenal hyperplasia (PUMAH) with concomitant glucocorticoid and androgen excess has never been encountered or studied.
Methods: We investigated a woman with a large, heterogeneous adrenal mass and severe ACTH-independent glucocorticoid and androgen excess, a biochemical presentation typically suggestive of adrenocortical carcinoma. The patient presented during pregnancy (22nd week of gestation) and reported an 18-month history of oligomenorrhoea, hirsutism, and weight gain. We undertook an exploratory study with detailed histopathological and genetic analysis of the resected adrenal mass and leukocyte DNA collected from the patient and her parents.
Results: Histopathology revealed benign macronodular adrenal hyperplasia. Imaging showed a persistently normal contralateral adrenal gland. Whole-exome sequencing of four representative nodules detected KDM1A germline variants p.G46S and likely pathogenic p.R269Dfs*7Whole-exome sequencing of four representative nodules detected inactivating KDM1A germline variants p.G46S and p.R269Dfs*7. Copy number variation analysis demonstrated an additional somatic loss of the KDM1A wild-type allele on chromosome 1p36.12 in all nodules. RNA-sequencing of a representative nodule showed low/absent KDM1A expression and increased GIPR expression compared to 52 unilateral sporadic adenomas and four normal adrenal glands. LH Receptor (LHCGR) expression was normal. Sanger sequencing confirmed heterozygous KDM1IA variants in both parents (father: p.R269Dfs*7; mother: p.G46S) who showed no clinical features of suggestive of glucocorticoid or androgen excessadrenal disease.
Conclusions: We investigated the first PUMAH associated with severe Cushing’s syndrome and concomitant androgen excess, suggesting pathogenic mechanisms involving KDM1A.  
SIGNIFICANCE STATEMENT
Adrenal tumours, mostly benign and non-functioning, are detected in 5% of the general population. The detection of an adrenal mass with concomitant glucocorticoid and androgen excess is considered pathognomonic highly suggestive of adrenocortical carcinoma. Macronodular adrenal hyperplasia typically involves both adrenal glands with associated glucocorticoid excess. In an exploratory study, we investigated a previously unencountered case of primary unilateral macronodular adrenal hyperplasia (PUMAH) with concomitant glucocorticoid and androgen excess. We identified germline KDM1A variants as previously reported in primary bilateral macronodular adrenal hyperplasia (PBMAH) and foodGIP-dependent Cushing’s syndrome. This study expands the phenotypic spectrum of inactivating KDM1A variants by describing the first case of PUMAH with combined cortisol and androgen excess, associated with KDM1A variants. These findings are essential considerations in the workup of patients with adrenal masses.