What is the role of ARMC5 (Armadillo Repeat-Containing 5) molecular biology in the management of a patient with primary macronodular adrenal hyperplasia (PMAH) and a family history of the condition?

ARMC5 Molecular Biology in Primary Macronodular Adrenal Hyperplasia

ARMC5 genetic testing should be performed in all patients with primary macronodular adrenal hyperplasia (PMAH), particularly those with cortisol-secreting disease or a family history, as germline mutations in this tumor suppressor gene are identified in 20-26% of apparently sporadic cases and up to 80% of familial presentations. 1, 2, 3

Understanding ARMC5 as a Tumor Suppressor Gene

ARMC5 (Armadillo Repeat-Containing 5) functions as a tumor suppressor gene that requires biallelic inactivation to drive adrenocortical tumorigenesis 1. The molecular mechanism follows a classic "two-hit" model:

• First hit: Germline heterozygous mutation inherited in an autosomal dominant pattern with incomplete penetrance 1, 4
• Second hit: Somatic mutation or loss of heterozygosity (LOH) at chromosome 16p11.2 in individual adrenal nodules 1, 5, 3

The incomplete penetrance is critical—only 10-20% of germline mutation carriers develop clinical disease, similar to BMPR2 mutations in pulmonary arterial hypertension 6. This suggests additional genetic or environmental modifiers are necessary to trigger disease manifestation 6.

Genetic Testing Strategy

When to Test

Perform ARMC5 sequencing in:

• All patients with bilateral adrenal macronodules (>1 cm) and cortisol excess 2, 4
• Patients with bilateral adrenal enlargement even without overt Cushing's syndrome 2
• Any patient with a family history of adrenal hyperplasia or Cushing's syndrome 1, 2

Do not test in:

• Non-secreting PBMAH cases, as mutations are rarely found in this subgroup 2

Testing Methodology

The comprehensive genetic workup should include 1, 3:

• Sequencing of all coding exons of ARMC5 to detect small mutations (missense, nonsense, frameshift, splice site variants)
• Copy number variation analysis to identify large deletions (present in 2% of cases) 3
• Tumor tissue analysis when available to identify the somatic second hit 1, 5

Genotype-Phenotype Correlations

Patients with ARMC5 mutations demonstrate distinct clinical features compared to non-mutated PMAH 2, 4:

Hormonal Profile

• More severe hypercortisolism: Higher midnight plasma cortisol, elevated 24-hour urinary free cortisol, and greater cortisol levels after dexamethasone suppression test 4
• Lower ACTH levels due to more pronounced negative feedback 4
• Higher prevalence of overt Cushing's syndrome rather than subclinical disease 4

Imaging Characteristics

• Larger adrenal glands bilaterally 2, 4
• Higher number of macronodules with multinodular phenotype 2
• More extensive bilateral involvement 2

Associated Comorbidities

• More severe hypertension requiring multiple antihypertensive agents 2
• Higher rates of diabetes mellitus 2

Family Screening Protocol

When an ARMC5 mutation is identified in the index case, implement the following cascade screening:

1. Offer genetic testing to all first-degree relatives (parents, siblings, children) 1, 2

2. Provide pre-test genetic counseling explaining the 50% inheritance risk and incomplete penetrance 6

3. For mutation-positive relatives, initiate surveillance:

   • Annual clinical assessment for signs of cortisol excess (weight gain, hypertension, glucose intolerance) 6
   • Baseline and periodic imaging (CT or MRI) to detect adrenal enlargement 7
   • Biochemical screening with morning cortisol, ACTH, and overnight dexamethasone suppression test 7, 8

4. Educate family members about symptoms requiring immediate evaluation: progressive weight gain, difficult-to-control hypertension, new-onset diabetes, or proximal muscle weakness 6

Molecular Genetic Variance

ARMC5 demonstrates remarkable genetic heterogeneity 5, 3:

• 146 different germline variants have been identified across the entire coding sequence 3
• Variant distribution: 46% missense, 45% truncating (nonsense/frameshift), 3% splice site, 4% in-frame, 2% large deletions 3
• Somatic variants: 104 different second-hit mutations documented, with each adrenal nodule potentially harboring a unique somatic event 5, 3

One remarkable case demonstrated 16 different somatic ARMC5 mutations across 20 adrenal nodules from a single patient, indicating polyclonal nodularity driven by extensive genetic instability in the context of germline ARMC5 deficiency 5.

Clinical Management Implications

Surgical Decision-Making

ARMC5 mutation status influences surgical planning:

• Mutation carriers have more aggressive disease requiring earlier intervention 4
• Bilateral adrenalectomy is typically necessary given the bilateral nature and progressive enlargement 2, 4
• Unilateral adrenalectomy is inadequate as contralateral disease will progress 2

Post-Surgical Considerations

Following bilateral adrenalectomy, patients require 9:

• Lifelong glucocorticoid replacement: Hydrocortisone 15-25 mg daily in divided doses 9
• Mineralocorticoid replacement if aldosterone deficiency develops 9
• Medical alert identification and emergency glucocorticoid supplies 9
• Stress-dose education for illness, injury, or surgery 9

Common Pitfalls to Avoid

1. Do not assume negative genetic testing excludes hereditary disease: Only 20-26% of PBMAH cases have identifiable ARMC5 mutations; other genetic causes likely exist 2, 4, 3

2. Do not delay family screening: Asymptomatic mutation carriers may have subclinical disease that benefits from early detection 6, 2

3. Do not overlook non-secreting cases in families: While rare, ARMC5 mutations can occasionally present without overt cortisol excess 2

4. Do not assume all missense variants are pathogenic: Functional studies demonstrating loss of apoptosis-inducing activity are necessary to confirm pathogenicity of novel missense substitutions 4, 3