title: Clinical features, diagnosis, treatment and molecular studies in paediatric Cushing's syndrome due to primary nodular adrenocortical hyperplasia.
abstract: BACKGROUND
  Primary nodular adrenocortical hyperplasia (PNAH) is a well recognized, but infrequently studied cause of paediatric Cushing's syndrome (CS).
  
  
  OBJECTIVE
  To assess presentation, diagnosis, radiological imaging, treatment and molecular analysis of patients with childhood-onset CS due to PNAH.
  
  
  METHODS
  Four males and two females (median age 12.9 years, range 10.9-16.9 years) were studied.
  
  
  RESULTS
  All had growth failure (mean height SDS -1.2; range -2.5-0.0), weight gain [mean body mass index (BMI) SDS 3.5; range 2.5-4.6] and clinical virilization, while five had hypertension [mean systolic blood pressure (SBP) 130 mmHg, diastolic blood pressure (DBP) 83 mmHg]. One patient had generalized lentigines, one had a tibial chondromyxomatous cyst and two had facial freckling. One patient had a family history of primary nodular adrenocortical disease. The diagnosis of CS was based on elevation of sleeping midnight serum cortisol and urinary free cortisol excretion, and impaired suppression of cortisol on both low- and high-dose dexamethasone suppression tests (DST). All patients had undetectable plasma ACTH with absent responses of both plasma ACTH and serum cortisol to an intravenous (i.v.) corticotrophin-releasing hormone (CRH) test. Computed tomography or magnetic resonance imaging showed normal or small adrenals, with nodules in two patients. All patients underwent bilateral adrenalectomy, performed by open (n = 2) or laparoscopic surgery (n = 4) at a mean of 0.4 years (range 0.2-0.8 years) from diagnosis. Hypercortisolaemia was treated preoperatively by metyrapone alone 0.50-0.75 g/day (n = 4), metyrapone 0.75-1.50 g/day + o'p'DDD/mitotane 1-2 g/day (n = 1), or ketoconazole (n = 1). Adrenal histology showed nodular cortical hyperplasia with shrinkage of intervening cortical tissue and pigmentation, present in four patients. Molecular analysis of the type 1-alpha regulatory subunit of protein kinase A (PRKAR1A) gene revealed a novel germline mutation in one patient. Postadrenalectomy, three patients, had catch-up growth with height velocities increasing from 3.0, 3.9 and 2.5-8.9, 8.3 and 9.0 cm/years, respectively. All six are well at a follow-up (mean 4.0 years; range 0.5-10.8 years).
  
  
  CONCLUSIONS
  PNAH was associated with cushingoid features, virilization and hypertension with a lack of cortisol suppression on high DST, undetectable plasma ACTH and absent cortisol and ACTH responses to CRH. Adrenals were normal or small on imaging. PRKAR1A gene analysis may be helpful in the assessment of these patients.
authors.affiliation: Department of Endocrinology, St Bartholomew's and The Royal London School of Medicine and Dentistry, London, UK.
authors.forename: H L
authors.initials: HL
authors.lastname: Storr
authors.forename: H
authors.initials: H
authors.lastname: Mitchell
authors.forename: F M
authors.initials: FM
authors.lastname: Swords
authors.forename: K M
authors.initials: KM
authors.lastname: Main
authors.forename: P C
authors.initials: PC
authors.lastname: Hindmarsh
authors.forename: P R
authors.initials: PR
authors.lastname: Betts
authors.forename: N J
authors.initials: NJ
authors.lastname: Shaw
authors.forename: D I
authors.initials: DI
authors.lastname: Johnston
authors.forename: A J L
authors.initials: AJ
authors.lastname: Clark
authors.forename: R H
authors.initials: RH
authors.lastname: Reznek
authors.forename: A B
authors.initials: AB
authors.lastname: Grossman
authors.forename: M O
authors.initials: MO
authors.lastname: Savage
mesh_terms: D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000150:complications* / Q000235:genetics / Q000601:surgery; D000315:Adrenalectomy; D002648:Child; D003480:Cushing Syndrome / Q000209:etiology* / Q000235:genetics / Q000601:surgery; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics; D005260:Female; D005438:Fludrocortisone / Q000627:therapeutic use; D005500:Follow-Up Studies; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000627:therapeutic use; D008297:Male; D017354:Point Mutation; D017422:Sequence Analysis, DNA
chemical_list: D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human; D017868:Cyclic AMP-Dependent Protein Kinases; D005438:Fludrocortisone; D006854:Hydrocortisone