Abstract
Background: Primary macronodular adrenal hyperplasia (PMAH) is an uncommon cause of Cushing’s syndrome. In some cases, this is an inherited disorder due to a mutation in the armadillo repeat-containing 5 (ARMC5) gene. Clinical Case: A 43-year-old African American woman presented to clinic with weight gain, worsening type 2 diabetes mellitus, and symptomatic hypertensive cardiomyopathy. Physical exam was significant for central obesity, bilateral supraclavicular fat pads, acanthosis nigricans and wide striae over the abdomen. Her serum cortisol was 13.8 mcg/dL after 1 mg of dexamethasone (n<1.8 mcg/dL), urinary cortisol was 180 mcg in 24 hours (n=3.5–45 mcg/24h) and two midnight salivary cortisol tests were 227 and 118 ng/dL (n<100 ng/dL). Her ACTH was 2.4 pg/mL (n=7.2–63.3 pg/mL). Computed tomography (CT) of the abdomen showed nodularity, diffuse thickening and low-density (<10 Hounsfield units) of the bilateral adrenal glands. She underwent bilateral adrenalectomy for a diagnosis of PMAH. Pathology showed nodular adrenocortical hyperplasia; the right and left adrenal glands measured 75 grams and 68 grams, respectively. She was started on hydrocortisone and fludrocortisone postoperatively. Over the following two years, she had a 68-pound weight loss, an 86% reduction in her daily insulin requirement and a 10% improvement in her left ventricular ejection fraction. Approximately two years later, the patient’s brother was referred for bilateral macronodular hyperplasia incidentally discovered on a CT of the abdomen. He had a history of hypertension and type 2 diabetes mellitus with cushingoid features on exam. His serum cortisol was 20.7 mcg/dL after 1 mg of dexamethasone, urinary cortisol was 65.1 mcg in 24 hours, two midnight salivary cortisol tests were 232 and 404 ng/dL and ACTH was 2.0 pg/mL. Upon obtaining further family history, the patients reported clinical features of Cushing’s syndrome in their paternal grandmother but denied features in either parent. The second patient had genetic testing which showed a mutation in the ARMC5 gene, c.1777C>T, p.R593W, a mutation previously described. Due to clinical signs of Cushing’s syndrome, he underwent bilateral adrenalectomy in which pathology showed right and left nodular adrenocortical hyperplasia measuring 110 and 73 grams, respectively. He is doing well postoperatively. The patients recently reported their aunt was diagnosed with PMAH and mild Cushing’s syndrome. She had a unilateral adrenalectomy of the larger adrenal gland and is doing well postoperatively. Conclusion: In some cases, Cushing’s syndrome is an inherited disorder. Autosomal dominant mutations in the ARMC5 gene are occasionally seen in PMAH, which causes less than 2% of endogenous Cushing’s syndrome. For all patients diagnosed with PMAH, clinicians should consider screening their family members with a dexamethasone suppression test.
Classification, diagnosis and treatment of ACTH-independent macronodular adrenal hyperplasia
