ARMC5 – Cushing Syndrome due to Macronodular Adrenal Hyperplasia

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is an autosomal dominant, ACTH-independent form of Cushing syndrome characterized by bilateral adrenal macronodules and hypercortisolism. Germline inactivating variants of ARMC5, followed by somatic second-hit mutations, underlie ~20–25% of apparently sporadic and ~80% of familial PBMAH cases ([PMID:25853793]). Loss of ARMC5 function leads to impaired apoptosis in adrenocortical cells and haploinsufficiency via nonsense-mediated mRNA decay, driving nodular hyperplasia and cortisol overproduction.

Genetic evidence includes screening of 98 unrelated PBMAH index cases, identifying germline ARMC5 mutations in 24 patients (26%) and segregation in at least 4 affected first-degree relatives, consistent with a two-hit tumor-suppressor mechanism ([PMID:25853793], [PMID:27094308]). Case series and familial studies report >300 probands across multiple cohorts, with recurrent frameshift and nonsense alleles distributed throughout ARMC5. A representative pathogenic variant is c.682C>T (p.Gln228Ter) ([PMID:29343284]).

Functional assays demonstrate that ARMC5 missense mutants and an in-frame deletion (p.Phe700del) fail to induce apoptosis in H295R and HeLa cells, unlike wild-type protein, confirming loss-of-function ([PMID:25853793]). In patient adrenal tissue, germline nonsense alleles trigger mRNA decay and reduced ARMC5 expression, supporting haploinsufficiency ([PMID:29343284]). No animal models have yet recapitulated the phenotype.

Phenotypically, ARMC5-mutated PBMAH patients exhibit more severe hypercortisolism, larger adrenals with higher nodule counts, and higher midnight cortisol and urinary free cortisol levels compared to non-mutated cases ([PMID:25853793]). Atypical presentations include proptosis (HP:0000520) as an initial sign of Cushing syndrome and hypogammaglobulinemia in rare cases.

No studies dispute the ARMC5–PBMAH association; all cohorts consistently identify germline and somatic hits in affected tissues. ARMC5 genotyping now informs early diagnosis, guides surgical decision-making, and enables familial screening for presymptomatic carriers.

Key Take-home: ARMC5 germline testing should be integrated into the diagnostic workup of PBMAH to confirm diagnosis, stratify disease severity, and facilitate family counseling.

References

• The Journal of Clinical Endocrinology and Metabolism | 2015 | ARMC5 Mutations in a Large Cohort of Primary Macronodular Adrenal Hyperplasia: Clinical and Functional Consequences PMID:25853793
• Journal of Medical Case Reports | 2018 | Extensive ARMC5 genetic variance in primary bilateral macronodular adrenal hyperplasia that started with exophthalmos: a case report PMID:29343284
• Endocrine | 2017 | A multicenter experience on the prevalence of ARMC5 mutations in patients with primary bilateral macronodular adrenal hyperplasia: from genetic characterization to clinical phenotype PMID:27094308

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