ARMC5 mutations are common in familial bilateral macronodular adrenal hyperplasia

Gagliardi, Lucia, Schreiber, Andreas W., Hahn, Christopher N., Feng, Jinghua, Cranston, Treena, Boon, Hannah, Hotu, Cheri, Oftedal, Bergithe E., Cutfield, Richard, Adelson, David L., Braund, Wilton J., Gordon, Richard D., Rees, D. Aled, Grossman, Ashley B., Torpy, David J. and Scott, Hamish S. (2014) ARMC5 mutations are common in familial bilateral macronodular adrenal hyperplasia. Journal of Clinical Endocrinology and Metabolism, 99 9: E1784-E1792. doi:10.1210/jc.2014-1265

Author Gagliardi, Lucia
Schreiber, Andreas W.
Hahn, Christopher N.
Feng, Jinghua
Cranston, Treena
Boon, Hannah
Hotu, Cheri
Oftedal, Bergithe E.
Cutfield, Richard
Adelson, David L.
Braund, Wilton J.
Gordon, Richard D.
Rees, D. Aled
Grossman, Ashley B.
Torpy, David J.
Scott, Hamish S.
Title ARMC5 mutations are common in familial bilateral macronodular adrenal hyperplasia
Formatted title
ARMC5 mutations are common in familial bilateral macronodular adrenal hyperplasia
Journal name Journal of Clinical Endocrinology and Metabolism   Check publisher's open access policy
ISSN 1945-7197
Publication date 2014-09-01
Year available 2014
Sub-type Article (original research)
DOI 10.1210/jc.2014-1265
Open Access Status
Volume 99
Issue 9
Start page E1784
End page E1792
Total pages 9
Place of publication Chevy Chase, MD, United States
Publisher Endocrine Society
Collection year 2015
Language eng
Formatted abstract

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.


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


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.


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 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 patient
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Medicine Publications
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