ARMC5 mutations are common in familial bilateral macronodular adrenal hyperplasia

Lucia Gagliardi, Andreas Schreiber, Christopher Hahn, Jinghua Feng, Treena Cranston, Hannah Boon, Cheri Hotu, Bergithe Oftedal, Rick Cutfield, David Adelson, Wilton Braund, Richard Gordon, Dafydd Rees, Ashley Grossman, David Torpy, Hamish Scott

    Research output: Contribution to journalArticlepeer-review

    88 Citations (Scopus)


    Conclusions: Our 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.

    Context: Bilateralmacronodularadrenalhyperplasia(BMAH)isarareformofadrenalCushing'ssyndrome. Familial cases have been reported, but at the timeweconducted this study, the genetic basis ofBMAHwas 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. Copyright

    Objective: Our objective was to identify the genetic basis of familial BMAH.

    Design: We 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.

    Results: 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.

    Original languageEnglish
    Pages (from-to)E1784-E1792
    Number of pages9
    JournalJournal of Clinical Endocrinology and Metabolism
    Issue number9
    Publication statusPublished - 1 Sept 2014


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