• Lucia Gagliardi, Andreas W Schreiber, Christopher N Hahn, Jinghua Feng, Treena Cranston, Hannah Boon, Cheri Hotu, Bergithe E Oftedal, Richard Cutfield, David L Adelson, Wilton J Braund, Richard D Gordon, D Aled Rees, Ashley B Grossman, David J Torpy, and Hamish S Scott.
• Endocrine and Metabolic Unit (L.G., D.J.T.), Royal Adelaide Hospital; Department of Genetics and Molecular Pathology (L.G., C.N.H., B.E.O., H.S.S.) and ACRF Cancer Genomics Facility (A.W.S., J.F., H.S.S.), Centre for Cancer Biology, SA Pathology; and School of Pharmacy and Medical Sciences (H.S.S.), Division of Health Sciences, University of South Australia, Adelaide SA 5000, Australia; Schools of Medicine (L.G., C.N.H., D.J.T., H.S.S.) and Molecular and Biomedical Science (A.W.S., J.F., D.L.A., H.S.S.), University of Adelaide SA 5005, Australia; Oxford Medical Genetics Laboratories (T.C., H.B.), Oxford University Hospitals National Health Service Trust, and Oxford Centre for Diabetes, Endocrinology and Metabolism (A.B.G.), Churchill Hospital, University of Oxford, Oxford OX3 7LE, United Kingdom; Department of Endocrinology (C.H.), Greenlane Clinical Centre, Auckland District Health Board, Auckland 1051, New Zealand; Department of Clinical Science (B.E.O.), University of Bergen, 5021 Bergen, Norway; Department of Endocrinology (R.C.), North Shore Hospital, Waitemata District Health Board, Auckland 0622, New Zealand; Department of Endocrinology (W.J.B.), Flinders Medical Centre, Bedford Park, SA 5042 Australia; School of Medicine (R.D.G.), University of Queensland, Brisbane QLD 4072, Australia; Endocrine Hypertension Research Centre (R.D.G.), Greenslopes and Princess Alexandra Hospitals, Brisbane QLD 4120, Australia; and Centre for Endocrine and Diabetes Sciences (D.A.R.), School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom.
• J. Clin. Endocrinol. Metab. 2014 Sep 1; 99 (9): E1784-92.

ContextBilateral 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.ObjectiveOur objective was to identify the genetic basis of familial BMAH.DesignWe performed whole exome capture and sequencing of 2 affected individuals from each of 4 BMAH families (BMAH-01, BMAH-02, BMAH-03, and BMAH-05). Based on clinical evaluation, there were 7, 3, 3, and 4 affected individuals in these families, respectively. Sanger sequencing of ARMC5 was performed in 1 other BMAH kindred, BMAH-06.ResultsExome 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.ConclusionsOur studies have detected ARMC5 mutations in 4 of 5 BMAH families tested, confirming that these mutations are a frequent cause of BMAH. Two of the 4 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.

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