Abstract
BACKGROUND: Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) is a known rare cause of Cushing’s syndrome (CS). A mutation in the armadillo repeat containing 5 (ARMC5) sequence is associated with up to 55% of PBMAH cases. Recent studies have linked ARMC5 mutations to presence of other benign neoplasias suggesting that ARMC5 could be a tumor suppressor gene. Case: 72-year-old female with a history of obesity, HTN, DM2, osteoporosis, multiple meningiomas, and hypercalcemia with recurrent kidney stones was incidentally found to have bilateral adrenal nodules on CT imaging. She had mild cushingoid features with truncal obesity and moon facies. She had multiple low dose dexamethasone suppression tests with AM cortisol levels in 17-21 ug/dL range (<1.8 ug/dL). She had late night salivary cortisols of 0.885ug/dL and 1.935ug/dL (0.022-0.254 ug/dl in PM). The overall clinical picture of obesity, HTN and DM2 in combination with biochemical testing and presence of bilateral adrenal adenomas was suggestive of CS secondary to PBMAH. On her evaluation for recurrent kidney stones she had a PTH of 107.2 pg/mL (15-65 pg/mL), and a calcium of 10.8 mg/dL (8.3-10.5 mg/dL). She was diagnosed with primary hyperparathyroidism. Imaging studies found a 1.1 cm ectopic parathyroid adenoma situated at the aortic pulmonary window. Surgical evaluation was performed and surgery was not offered given the precarious location of the parathyroid tumor. She had a known history of four meningiomas, two of which were resected and two considered uncresectable. PBMAH in presence of all her other medical comorbidities prompted genetic evaluation for the patient. Analysis revealed a heterozygous ARMC5 mutation. Given the familial pattern of inheritance associated with ARMC5 mutations, patient’s daughter also underwent genetic testing. Daughter tested positive for the mutation as well. Patient was offered surgical and medical therapy options for her PBMAH. She is currently being evaluated for an unilateral adrenalectomy. Discussion: The pathophysiology of CS from PBMAH remains poorly understood leading to an insidious delay in diagnosis and treatment. Inactivating ARMC5 mutations of familial origins are known genetic triggers for development of PBMAH. ARMC5 is also a proposed tumor suppressor gene whose proteins are found in endocrine tissues all over body. Mutation of ARMC5 gene potentially can lead to multi-glandular tumor syndromes. Screening PBMAH patients and their family members for ARMC5 mutations may lead to earlier CS diagnosis/treatment times as well as better understanding of the gene’s neoplastic potential. References: Faucz, Fabio R., et al. “Macronodular Adrenal Hyperplasia Due to Mutations in an Armadillo Repeat Containing 5 (ARMC5) Gene: A Clinical and Genetic Investigation.” The Journal of Clinical Endocrinology & Metabolism, vol. 99, 2014.
Inactivation of the Tumor Suppressor Gene on 11q13 in Brothers with Familial Acrogigantism without Multiple Endocrine Neoplasia Type 11
