title: Familial vasopressin-sensitive ACTH-independent macronodular adrenal hyperplasia (VPs-AIMAH): clinical studies of three kindreds.
abstract: OBJECTIVE
  Cushing's syndrome due to familial ACTH-independent macronodular adrenal hyperplasia (AIMAH) has been reported in small kindreds. In vasopressin-sensitive AIMAH (VPs-AIMAH), VP stimulates an aberrant, ACTH-independent increase in cortisol. The aims of this study were to (i) delineate the preclinical phenotype of VPs-AIMAH in a three-generation kindred (AIMAH-01) and two smaller kindreds (AIMAH-02 and AIMAH-03) and (ii) investigate the aetiology of VP sensitivity in AIMAH-01.
  
  
  METHODS
  Clinical studies of three kindreds for adrenal tumours or early Cushing's and molecular studies of adrenal tumours (AIMAH-01).
  
  
  METHODS
  Thirty-three individuals, from three kindreds, were screened for perturbations of the hypothalamic-pituitary-adrenal axis or adrenal tumours.
  
  
  METHODS
  Patients underwent clinical, biochemical and adrenal imaging investigations. Evaluation included low-dose (1 IU/70 kg) VP stimulation. Adrenal VP receptor (AVPR1A, AVPR1B, AVPR2) expression (AIMAH-01) was assessed using RT-PCR and immunohistochemistry (IHC). IHC for VP was also performed.
  
  
  RESULTS
  AIMAH-01 had three siblings with Cushing's, and four individuals with suppressed ACTH/aberrant VP responses and/or adrenal nodules. In AIMAH-02, a father and son were affected. AIMAH-03 had three siblings with Cushing's. RT-PCR showed adrenal overexpression of AVPR1A and AVPR1B. IHC detected AVPR1A. The adrenal tumour from one patient also stained weakly for VP and AVPR2.
  
  
  CONCLUSIONS
  Adrenal nodules, suppressed ACTH and increased VP sensitivity may represent preclinical disease, allowing early detection, and treatment, of affected individuals. In AIMAH-01, increased VP sensitivity may be due to adrenal VP receptor overexpression. In these kindreds, VPs-AIMAH is familial, and autosomal dominant inheritance is most likely.
authors.affiliation: Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, South Australia 5000, Australia. lucia.gagliardi@health.sa.gov.au
authors.forename: Lucia
authors.initials: L
authors.lastname: Gagliardi
authors.forename: Cheri
authors.initials: C
authors.lastname: Hotu
authors.forename: Graeme
authors.initials: G
authors.lastname: Casey
authors.forename: Wilton J
authors.initials: WJ
authors.lastname: Braund
authors.forename: King-Hwa
authors.initials: KH
authors.lastname: Ling
authors.forename: Thomas
authors.initials: T
authors.lastname: Dodd
authors.forename: James
authors.initials: J
authors.lastname: Manavis
authors.forename: Peter G
authors.initials: PG
authors.lastname: Devitt
authors.forename: Richard
authors.initials: R
authors.lastname: Cutfield
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Rudzki
authors.forename: Hamish S
authors.initials: HS
authors.lastname: Scott
authors.forename: David J
authors.initials: DJ
authors.lastname: Torpy
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics / Q000378:metabolism; D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D003480:Cushing Syndrome / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D017483:Receptors, Vasopressin / Q000235:genetics / Q000378:metabolism; D014667:Vasopressins / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D017483:Receptors, Vasopressin; D014667:Vasopressins; D000324:Adrenocorticotropic Hormone