title: Clinical, biochemical, and molecular characterization of macronodular adrenocortical hyperplasia of the zona reticularis: a new syndrome.
abstract: BACKGROUND
  Macronodular adrenocortical hyperplasia classically presents with progressive hypercortisolemia and Cushing syndrome. We describe a 29-yr-old man with massive macronodular adrenocortical hyperplasia without hypercortisolemia but rather markedly elevated and nonsuppressible production of dehydroepiandrosterone (DHEA) and its sulfate (DHEAS).
  
  
  OBJECTIVE
  To characterize the clinical and molecular features of this case and to determine whether the tissue biochemically resembles the zona reticularis or fetal adrenal.
  
  
  METHODS
  University clinic, hospital, and laboratories.
  
  
  METHODS
  Static and dynamic blood and urine testing were performed preoperatively. Tissue was studied by light microscopy, immunoblot, RNA microarray, and enzyme assay.
  
  
  METHODS
  A 29-yr-old man with incidentally discovered bilateral adrenal enlargement.
  
  
  METHODS
  Bilateral adrenalectomy.
  
  
  METHODS
  Molecular studies compared with control samples.
  
  
  RESULTS
  Hypercortisolism and 21-hydroxylase deficiency were excluded. DHEA, DHEAS, and 17-hydroxypregnenolone were markedly elevated and did not suppress with dexamethasone 2 mg/d for 4 d. Homogenates of the adrenals demonstrated high 17-hydroxylase, good 17,20-lyase, and low or absent 21-hydroxylase and 3β-hydroxysteroid dehydrogenase activities. Immunoblots confirmed robust expression of cytochrome P450c17 and AKR1C3 but not P450c21. Microarray analysis demonstrated high CYP11A1 and CYP17A1 expression but low or absent HSD3B1, HSD3B2, and CYP21A2 expression. Expression of mRNA for cytochrome b(5) (CYB5A) and AKR1C3, markers of the zona reticularis, were markedly elevated.
  
  
  CONCLUSIONS
  This is the first case of macronodular hyperplasia of the adrenal zona reticularis confirmed with studies of enzyme activity, mRNA expression, and protein identification. We speculate that this condition can be clinically silent in men but might cause severe hyperandrogenemia in women.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-8857, USA.
authors.forename: Hans K
authors.initials: HK
authors.lastname: Ghayee
authors.forename: Juilee
authors.initials: J
authors.lastname: Rege
authors.forename: Lori M
authors.initials: LM
authors.lastname: Watumull
authors.forename: Fiemu E
authors.initials: FE
authors.lastname: Nwariaku
authors.forename: Kelley S
authors.initials: KS
authors.lastname: Carrick
authors.forename: William E
authors.initials: WE
authors.lastname: Rainey
authors.forename: Walter L
authors.initials: WL
authors.lastname: Miller
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Auchus
mesh_terms: D000311:Adrenal Glands / Q000473:pathology; D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000315:Adrenalectomy; D000328:Adult; D015153:Blotting, Western; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D003687:Dehydroepiandrosterone / Q000378:metabolism; D005333:Fetus / Q000473:pathology; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D008297:Male; D046228:Microarray Analysis; D012313:RNA / Q000096:biosynthesis / Q000235:genetics / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013577:Syndrome; D013739:Testosterone / Q000097:blood; D014057:Tomography, X-Ray Computed; D015385:Zona Reticularis / Q000473:pathology*
chemical_list: D018076:DNA, Complementary; D013739:Testosterone; D003687:Dehydroepiandrosterone; D012313:RNA; D006854:Hydrocortisone