How does ethnicity clustering impact the management of primary macronodular adrenal hyperplasia (PMAH) in patients with a family history of the condition and potential ARMC5 (Armadillo Repeat-Containing 5) mutations?

Management of PMAH with Family History and ARMC5 Mutations

When ARMC5 mutations are identified in PMAH patients with family history, implement mandatory cascade genetic screening of all first-degree relatives with 50% inheritance risk counseling, initiate annual surveillance in mutation-positive relatives, and plan for bilateral adrenalectomy in the index case given the progressive bilateral nature of disease in mutation carriers. 1

Genetic Testing Strategy

Comprehensive ARMC5 genetic analysis should include both sequencing of all coding exons to detect small mutations and copy number variation analysis to identify large deletions. 1 This dual approach is critical because germline deletions (such as deletions of exons 1-5) have been documented in familial PMAH cases and would be missed by sequencing alone. 2

Prevalence and Detection Rates

• ARMC5 mutations are identified in approximately 71% of Japanese patients with PMAH and in 10 of 14 patients (71%) in one cohort, making it the most common genetic cause of cortisol-secreting PMAH. 3
• In Italian cohorts, ARMC5 mutations were found only in cortisol-secreting PBMAH patients (11 of 53 cases), never in non-secreting cases. 4
• Certain variants may represent ethnic-specific hotspots—the p.R619* variant was found in five unrelated Japanese patients, suggesting potential ethnicity clustering. 3

Family Screening Protocol

When an ARMC5 mutation is identified in the index case, cascade screening must be implemented with specific components: 1

• Offer genetic testing to all first-degree relatives with pre-test genetic counseling explaining the 50% autosomal dominant inheritance risk. 1
• Explain incomplete penetrance clearly—only 10-20% of germline mutation carriers develop clinical disease, similar to BMPR2 mutations in pulmonary arterial hypertension. 1
• Document that asymptomatic or presymptomatic pathogenic variant carriers are commonly found among family members of affected patients. 3

Surveillance for Mutation-Positive Relatives

For relatives who test positive for ARMC5 mutations, initiate structured surveillance: 1

• Annual clinical assessment for signs of cortisol excess (hypertension, diabetes, weight gain, proximal muscle weakness). 1
• Baseline and periodic imaging (CT or MRI) to detect adrenal enlargement. 1
• Biochemical screening with morning cortisol, ACTH, and 1-mg dexamethasone suppression test. 4

Clinical Phenotype of ARMC5 Mutation Carriers

ARMC5 mutation-positive patients demonstrate distinct clinical characteristics that influence management:

• Significantly higher basal cortisol levels compared to mutation-negative PMAH patients (p = 0.062). 4
• More severe hypertension and diabetes mellitus (p < 0.05). 4
• Significantly larger adrenal glands with a characteristic multinodular phenotype (p < 0.01). 4
• Age-dependent cortisol hypersecretion pattern, with progressive worsening over time. 3

Surgical Planning Considerations

ARMC5 mutation status directly influences surgical decision-making: 1

• Mutation carriers have more aggressive disease requiring earlier surgical intervention. 1
• Bilateral adrenalectomy is typically necessary given the bilateral nature and progressive enlargement characteristic of ARMC5-related disease. 1
• Unilateral adrenalectomy is generally inadequate because the disease is genetically driven to affect both glands. 4

Post-Surgical Management

Following bilateral adrenalectomy, patients require comprehensive lifelong hormone replacement: 1

• Lifelong glucocorticoid replacement therapy. 1
• Mineralocorticoid replacement if aldosterone deficiency develops. 1
• Medical alert identification for emergency situations. 1
• Emergency glucocorticoid supplies for stress dosing. 1

Molecular Mechanisms and Second-Hit Events

ARMC5 functions as a tumor suppressor gene requiring biallelic inactivation for disease manifestation:

• Germline heterozygous mutations represent the first hit. 5
• Somatic mutational events (second hits) were identified in adrenal nodules of 4-5 patients in multiple studies. 4, 5
• Loss of heterozygosity (LOH) or second-hit mutations occur independently in each adrenal nodule, explaining the multinodular phenotype. 5, 2

Management When Genetic Testing is Negative

If ARMC5 testing is negative but clinical phenotype strongly suggests PMAH with family history: 6

• Do not dismiss the clinical diagnosis solely because genetic testing is negative—approximately 29% of PMAH cases lack identifiable ARMC5 mutations. 3
• Treat based on the clinical syndrome and organ involvement rather than waiting for genetic confirmation. 6
• Use phenotypic screening of at-risk relatives when genetic testing is unavailable or negative. 6
• Provide genetic counseling based on empiric recurrence risks when no mutation is identified. 6

Critical Pitfalls to Avoid

• Never delay treatment waiting for genetic confirmation—management should be initiated based on clinical diagnosis. 6
• Do not assume family members are unaffected without screening—asymptomatic carriers are common. 3, 7
• Avoid unilateral adrenalectomy in confirmed ARMC5 mutation carriers due to the bilateral progressive nature of disease. 1
• Do not overlook large deletions by using sequencing alone—copy number variation analysis is essential. 1, 2