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.