A novel pathogenic variant of ARMC5 in a patient with primary bilateral macronodular adrenal hyperplasia: a case...

Primary bilateral macronodular adrenal hyperplasia (PBMAH), also known as adrenocorticotropic hormone (ACTH)-independent macronodular adrenal hyperplasia, is a rare cause of endogenous Cushing's syndrome. In many familial cases of PBMAH, the variants in armadillo repeat containing 5 (ARMC5) gene are found to be associated with the disease. Here, we report a case of PBMAH harboring a novel frameshift variant in ARMC5 gene, which has not been previously reported in the literature.

A 67-year-old woman was referred due to the clinical features of Cushing's syndrome. Radiological imaging and hormonal testing were carried out. The serum levels of cortisol were remarkably increased at late night and did not suppress even after 1 mg of dexamethasone administration, while the plasma levels of ACTH hormone were decreased significantly. The patient underwent unilateral left-sided laparoscopic adrenalectomy, and the diagnosis of PBMAH was substantiated by histopathological analysis. Moreover, the partial envelope was incomplete and the cell proliferation index was low. Specifically, inhibin α-subunit ( +), syn focal ( +), Ki-67 ~ 3% ( +), CgA (-) and CEA (-) were observed. DNA sequencing data revealed that a novel frameshift variant (c.363_373delGCCAGTGCGCC, p.Pro122Alafs*61) was identified in ARMC5 gene. However, this variant was not detected in the daughter of the patient. The rest of the family members, including her sister, son and two brothers, were not consented for genetic testing.

Early detection of ARMC5 variant status and familial screening might have important clinical implications for the diagnosis and prognosis of PBMAH patients. A novel ARMC5 frameshift variant (c.363_373delGCCAGTGCGCC, p.Pro122Alafs*61) was identified to be associated with the pathogenesis of PBMAH. ARMC5 sequencing may improve the identification of a causative gene variant for PBMAH and allow earlier diagnosis of this disease.