title: An unusual case of an ACTH-secreting macroadenoma with a germline variant in the aryl hydrocarbon receptor-interacting protein (AIP) gene.
abstract: A patient of Cushing's disease (CD) characterized by a large tumor and only subtle symptoms of hormonal hypersecretion was examined. The patient had a germline variant in the aryl hydrocarbon receptor-interacting protein (AIP) gene. A 50-year-old male presenting with headache was diagnosed with a large pituitary tumor by magnetic resonance imaging (MRI). His visual fields were intact and he exhibited no features of CD. Owing to an exuberant response to synacthen, an overnight dexamethasone suppression test was performed revealing inadequate suppression of plasma cortisol (419 nmol/l). Owing to tumor growth and visual field impairment, he underwent transsphenoidal surgery and developed hypocortisolemia. The pathology specimen revealed a sparsely granulated corticotrope adenoma. Postoperative MRI showed a large tumor remnant. The patient developed skin hyperpigmentation and a synacthen test demonstrated high basal and stimulated cortisol levels; an overnight dexamethasone suppression test showed no suppression (791 nmol/l) and elevated plasma ACTH levels (135 ng/l). A transcranial operation was performed followed by radiotherapy. Two months after radiotherapy, he developed secondary adrenocortical failure. Genetic testing revealed an AIP variant of unknown significance (p.R16H) without loss of the normal AIP allele in the tumor. A literature review showed ten CD patients with AIP gene variants, of whom five (including our case) were p.R16H. CD is occasionally dominated by pituitary tumor growth rather than symptoms of hypersecretion. The particular AIP gene variant identified in our patient is shared by four other reported cases of CD. Future studies are needed to assess whether the reported AIP gene variant is more than just coincidental.
  
  
  CONCLUSIONS
  CD is occasionally dominated by pituitary tumor growth rather than symptoms of hypersecretion.Resolution of both tumor remnant and hormonal hypersecretion may occur within 2 months after postoperative radiotherapy.The particular AIP gene variant identified in our patient is shared by four other reported cases of CD.
authors.affiliation: Department of Endocrinology and Internal Medicine, Aarhus University Hospital , Aarhus , Denmark.
authors.forename: Pia T
authors.initials: PT
authors.lastname: Dinesen
authors.affiliation: Department of Endocrinology and Internal Medicine, Aarhus University Hospital , Aarhus , Denmark.
authors.forename: Jakob
authors.initials: J
authors.lastname: Dal
authors.affiliation: Department of Endocrinology, Bart's and the London School of Medicine, Queen Mary University of London , London , UK.
authors.forename: Plamena
authors.initials: P
authors.lastname: Gabrovska
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital , Aarhus , Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Gaustadnes
authors.affiliation: Department of Endocrinology and Internal Medicine, Aarhus University Hospital , Aarhus , Denmark ; Department of Molecular Medicine, Aarhus University Hospital , Aarhus , Denmark.
authors.forename: Claus H
authors.initials: CH
authors.lastname: Gravholt
authors.affiliation: Department of Molecular Genetics, Royal Devon and Exeter, Foundation Trust , Exeter , UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Stals
authors.affiliation: Department of Endocrinology and Internal Medicine, Aarhus University Hospital , Aarhus , Denmark.
authors.forename: Judit
authors.initials: J
authors.lastname: Denes
authors.affiliation: Department of Pathology, University Health Network , Toronto, Ontario , Canada ; Laboratory Medicine and Pathobiology, University of Toronto , Toronto, Ontario , Canada.
authors.forename: Sylvia L
authors.initials: SL
authors.lastname: Asa
authors.affiliation: Department of Endocrinology, Bart's and the London School of Medicine, Queen Mary University of London , London , UK.
authors.forename: Márta
authors.initials: M
authors.lastname: Korbonits
authors.affiliation: Department of Endocrinology and Internal Medicine, Aarhus University Hospital , Aarhus , Denmark.
authors.forename: Jens O L
authors.initials: JO
authors.lastname: Jørgensen