Acth-Independent Macronodular Adrenal Hyperplasia 2


A number sign (#) is used with this entry because ACTH-independent macronodular adrenal hyperplasia-2 (AIMAH2) is caused by heterozygous germline mutation in the ARMC5 gene (615549) coupled with somatic mutation of the other allele in adrenal tumors.

For a discussion of genetic heterogeneity of ACTH-independent macronodular adrenal hyperplasia, see 219080.


ACTH-independent macronodular adrenal hyperplasia-2 is an autosomal dominant tumor susceptibility with syndromic incomplete penetrance, as a second hit to the ARMC5 gene is required to develop macronodular hyperplasia (Assie et al., 2013).

Clinical Features

Assie et al. (2013) reported 18 patients (9 female) with germline ARMC5 mutations. Their ages ranged from 30 to 73 years. Corticotropin levels varied between less than 5 and less than 10 picograms per milliliter. Plasma cortisol levels after 1 milligram of dexamethasone ranged from 3.6 to 36.7 micrograms per deciliter. Urinary cortisol levels ranged from 37 to 1,463 micrograms per 24 hours. Fifteen patients had clinical Cushing syndrome and 3 had subclinical Cushing syndrome.

Molecular Genetics

Assie et al. (2013) identified ARMC5 mutations in tumors from 18 (55%) of 33 patients with macronodular adrenal hyperplasia. They also found loss of heterozygosity at chromosome 16p11.2 in 8 (24%) of 33 patients for whom data were available. In all cases, both alleles of ARMC5 carried mutations: 1 germline and the other somatic. In 4 patients with germline ARM5C mutations, Assie et al. (2013) identified different mutations on the other ARMC5 allele in nodules. Assie et al. (2013) performed transcriptome-based classification of corticotropin-independent macronodular adrenal hyperplasia, and found that ARMC5 mutations influenced gene expression in a predictable manner.

Alencar et al. (2014) reported a heterozygous germline missense variant in the ARMC5 gene (615549.0007) in a very large Brazilian family segregating primary macronodular adrenal hyperplasia. Seven additional ARMC5 variants were subsequently identified in 5 of 21 patients with apparently sporadic primary macronodular adrenal hyperplasia and in 2 of 3 families with the disease. Further molecular analysis identified a somatic mutational event in 4 patients whose adrenal tissue was available.

Faucz et al. (2014) sequenced and characterized 34 patients with macronodular adrenal hyperplasia and found germline ARMC5 mutations in 15 of them (44.1%). However, in silico analysis predicted only half of these mutations to be pathogenic. All patients carrying a clearly pathogenic ARMC5 mutation had clinical Cushing syndrome, compared with 14 (52%) of 27 of those without mutations or with benign mutations in ARMC5.

Gagliardi et al. (2014) used whole-exome or Sanger sequencing to identify mutations in the ARMC5 gene in 4 of 5 families with bilateral macronodular adrenal hyperplasia. Three of these families had been described by Gagliardi et al. (2009). No mutation was identified in the fifth family.