SFEBES2023 Featured Clinical Case Posters Section (10 abstracts)
Primary Unilateral Macronodular Adrenal Hyperplasia (PUMAH) With Concomitant Glucocorticoid And Androgen Excess due to KDM1A inactivation and constitute MC2R activation
Yasir Elhassan 1 , Silke Appenzeller 2 , Laura Landwehr 3 , Dillon Popat 4 , Lorna Gilligan 1 , Edwina Goh 5 , Salvador Diaz-Cano 6 , Stefan Kircher 7 , Susanne Gramlich 7 , Robert Sutcliffe 8 , Shakila Thangaratinam 1 , Li Chan 4 , Martin Fassnacht 3 , Wiebke Arlt 1 & Cristina Ronchi 1
1Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom. 2Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Würzburg, Germany. 3Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg, Würzburg, Germany. 4Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom. 5Birmingham Women’s Hospital, Birmingham, United Kingdom. 6Department of Pathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom. 7Department of Pathology, University of Würzburg, Würzburg, Germany. 8The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
Clinical vignette: We investigated a 33-year-old woman diagnosed during pregnancy with a 7cm unilateral adrenal mass associated with severe ACTH-independent glucocorticoid and androgen excess, a steroid phenotype usually indicative of adrenocortical carcinoma. Pregnancy had been achieved with in-vitro fertilisation on the assumption of underlying PCOS. Neonatal death occurred soon after emergency delivery due to foetal growth arrest at 26 weeks gestation. Histopathology after post-pregnancy unilateral adrenalectomy showed tumour-like macronodular adrenocortical hyperplasia. Postoperatively, the clinical and biochemical phenotype resolved. The contralateral adrenal had normal size and morphology. The patient spontaneously conceived three months later and delivered a healthy baby. Workup: Germline mutations in ARMC5 were excluded. We performed whole-exome sequencing on four representative hyperplastic cortical nodules. We detected germline variants p.G46S and p.R269Dfs*7 in KDM1A and p.M255I in the gene encoding for the ACTH receptor (MC2R). Copy number variation analysis showed clonally related nodules and demonstrated an additional somatic loss of the KDM1A wild-type allele on chromosome 1p36.12 in all nodules. RNA-sequencing on a representative nodule showed low/absent expression of KDM1A and a high expression of the gene GIPR compared to 52 adenomas and 4 normal adrenals, suggesting a similar pathogenic mechanism as recently described in primary bilateral macronodular adrenal hyperplasia associated with food-dependant Cushing Syndrome. Functional in vitro analysis of the MC2R variant demonstrated constitutive activation of receptor activity. Sanger sequencing confirmed germline KDMIA p.R269Dfs*7 variant in the father and both KDM1A p.G46S and MC2R p.M255I variants in the mother. Clinical assessment of the parents showed no features of glucocorticoid or androgen excess.
Conclusion: We present the first case of primary unilateral macronodular adrenocortical hyperplasia (PUMAH) associated with Cushing’s syndrome and concomitant androgen excess and suggest pathogenic mechanisms involving KDM1A and MC2R.
Volume 94
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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