Endocrine Abstracts

Introduction: Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a highly heterogeneous disorder and is the cause of <2% of cases of Cushing’s syndrome. Around 20-25% of patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) have a mutation in ARMC5.

Case report: 47 year old gentleman was incidentally found to have bilateral adrenal lesions when he had a CT scan of his chest performed for chest and back pains. He had a past history of hypertension, diagnosed 8 years ago, on treatment. He had plethoric face but no striae or easy bruising, but had central obesity and thin legs. His BMI was 33 on presentation. CT scan of adrenals showed bilateral macronodular hyperplasia (right adrenal mass 5 cm and left adrenal mass 3.5 cm) not typical of adrenal adenoma. Random ACTH was suppressed. Overnight dexamethasone suppression test, low dose and high dose dexamethasone suppression tests failed to suppress cortisol with suppressed ACTH levels. Dexamethasone level, post dexamethasone suppression test showed adequate absorption/metabolism. 24 hour urinary cortisol was normal. MRI pituitary showed normal pituitary gland with no abnormal enhancement. He had slightly elevated mid night salivary cortisol and cortisone. His 17OHP level was normal. His urinary steroid profiling was normal (except low 5 alfa reductase level). His 24 hour urine catecholamines were negative and plasma renin and aldosterone level was normal. His DEXA scan was normal. All his investigations were in keeping with ACTH independent Cushing’s disease. He underwent bilateral adrenalectomy and subsequently commenced on replacement dose of steroids. In view of radiological and histological diagnosis of bilateral macronodular adrenal hyperplasia, he was consented for screening for genetic mutations and this showed heterozygous ARMC5 mutation NM_001105247.1:c.2097_2099del p.(Phe700del) which was likely to be pathogenic and associated with ACTH independent macronodular adrenal hyperplasia Type 2. This particular variant has been reported in another case previously in 2015, but not reported in gnomAD database and so is only the second patient reported with such a variant in literature, as far as we know.

Conclusion: A significant proportion of what is thought to be sporadic cases of bilateral macronodular adrenal hyperplasia are due to ARMC5 genetic mutations and family history is not a reliable indicator. Patients with large multinodular adrenal gland and cortisol excess may be more likely to harbour ARMC5 germline mutation and there should be a low threshold for genetic testing.