Poster Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2014

ARMC5 mutations are common in Familial Bilateral Macronodular Adrenal Hyperplasia (#247)

Lucy Gagliardi 1 2 3 , Andreas W Schreiber 4 5 , Chris N Hahn 2 3 , Jinghua Feng 4 5 , Treena Cranston 6 , Hannah Boon 6 , Cheri Hotu 7 , Bergithe E Oftedal 2 8 , Richard Cutfield 9 , David L Adelson 5 , Wilton J Braund 10 , Richard D Gordon 11 12 , D A Rees 13 , Ashley B Grossman 14 , David J Torpy 1 3 , Hamish S Scott 2 3 4 5 15
  1. Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, SA, Australia
  2. Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia
  3. School of Medicine, University of Adelaide, Adelaide, SA, Australia
  4. ACRF Cancer Genomics Facility, Centre for Cancer Biology, SA Pathology, Adelaide, SA, AUSTRALIA
  5. School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA, Australia
  6. Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Trust, Oxford, LE, United Kingdom
  7. Department of Endocrinology, Auckland District Health Board, Auckland, New Zealand
  8. Department of Clinical Science, University of Bergen, Bergen, Norway
  9. Department of Endocrinology, Waitemata District Health Board, Auckland, New Zealand
  10. Department of Endocrinology, Flinders Medical Centre, Adelaide, SA, Australia
  11. School of Medicine, University of Queensland, Brisbane, Qld, Australia
  12. Endocrine Hypertension Research Centre, Greenslopes and Princess Alexandra Hospitals, Brisbane, Qld, Australia
  13. Centre for Endocrine and Diabetes Sciences, School of Medicine, University of Cardiff, Cardiff, United Kingdom
  14. Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Oxford, United Kingdom
  15. School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Adelaide, SA, Australia

Bilateral macronodular adrenal hyperplasia (BMAH) is a rare form of adrenal Cushing’s syndrome. Familial cases have been reported but at the time we conducted this study, the genetic basis of BMAH was unknown. Recently, germline variants of armadillo repeat containing 5 (ARMC5) in patients with isolated BMAH, and somatic, second-hit mutations in tumor nodules were identified.1
To identify the genetic basis of familial BMAH.
We performed whole exome capture and sequencing of two affected individuals from each of three BMAH families we have previously described (BMAH-01, BMAH-02, BMAH-03) and one additional kindred (BMAH-05).2 Based on clinical evaluation there were seven, three, three and four affected individuals in these families, respectively. Sanger sequencing of ARMC5 was performed in one other BMAH kindred, BMAH-06.
Exome sequencing identified novel variants: Chr16:g.31477540, c.2139delT, p.(Thr715Leufs*1) (BMAH-02) and Chr16:g.31473811, c.943C>T, p.(Arg315Trp) (BMAH-03) in ARMC5 (GRch37/hg19), validated by Sanger sequencing. BMAH-01 had a recently reported mutation Chr16:g.31476121, c.1777C>T, p.(Arg593Trp). Sanger sequencing of ARMC5 in BMAH-06 identified a previously reported mutation, Chr16:g. 31473688; c.799C>T, p.(Arg267*). The genetic basis of BMAH in BMAH-05 was not identified.
Our studies have detected ARMC5 mutations in four of five BMAH families tested, confirming that these mutations are a frequent cause of BMAH. Two of the four families had novel mutations, indicating allelic heterogeneity. Preclinical evaluation did not predict mutation status. The ARMC5 negative family had unusual prominent hyperaldosteronism. Further studies are needed to determine the penetrance of BMAH in ARMC5 mutation-positive relatives of affected patients, the practical utility of genetic screening and genotype-phenotype correlations.

  1. Assié G, Libé R, Espiard S, Rizk-Rabin M, Guimier A, Luscap W, Barreau O, Lefèvre L, Sibony M, Guignat L, Rodriguez S, Perlemoine K, René-Corail F, Letourneur F, Trabulsi B, Poussier A, Chabbert-Buffet N, Borson-Chazot F, Groussin L, Bertagna X, Stratakis CA, Ragazzon B, Bertherat J. ARMC5 Mutations in Macronodular Adrenal Hyperplasia with Cushing’s syndrome. New Engl J Med 2013; 369:2105-14
  2. Gagliardi L, Hotu C, Casey G, Braund WJ, Ling KH, Dodd T, Manavis J, Devitt PG, Cutfield R, Rudzki Z, Scott HS, Torpy DJ. Familial Vasopressin-sensitive ACTH-Independent Macronodular Adrenal Hyperplasia (VPs-BMAH): Clinical Studies of Three Kindreds. Clin Endocrinol (Oxf) 2009; 70:883-91.