ARMC5 mutation in a Portuguese family with primary bilateral macronodular adrenal hyperplasia (PBMAH)

Abstract

SummaryPBMAH is a rare etiology of Cushing syndrome (CS). Familial clustering suggested a genetic cause that was recently confirmed, after identification of inactivating germline mutations in armadillo repeat-containing 5 (ARMC5) gene. A 70-year-old female patient was admitted due to left femoral neck fracture in May 2014, in Orthopedics Department. During hospitalization, hypertension (HTA) and hypokalemia were diagnosed. She presented with clinical signs of hypercortisolism and was transferred to the Endocrinology ward for suspected CS. Laboratory workup revealed: ACTH <5 pg/mL; urinary free cortisol (UFC), 532 µg/24 h (normal range: 20–90); failure to suppress the low-dose dexamethasone test (0.5 mg every 6 h for 48 h): cortisol 21 µg/dL. Abdominal magnetic resonance imaging (MRI) showed enlarged nodular adrenals (right, 55 × 54 × 30 mm; left, 85 × 53 × 35 mm), and she was submitted to bilateral adrenalectomy. In 2006, this patient’s 39-year-old daughter had been treated by one of the authors. She presented with severe clinical and biological hypercortisolism. Computed tomography (CT) scan showed massively enlarged nodular adrenals with maximal axis of 15 cm for both. Bilateral adrenalectomy was performed. In this familial context of PBMAH, genetic study was performed. Leucocyte DNA genotyping identified in both patients the same germline heterozygous ARMC5 mutation in exon 1 c.172_173insA p.I58Nfs*45. The clinical cases herein described have an identical phenotype with severe hypercortisolism and huge adrenal glands, but different ages at the time of diagnosis. Current knowledge of inheritance of this disease, its insidious nature and the well-known deleterious effect of hypercortisolism favor genetic study to timely identify and treat these patients.Learning points:PBMAH is a rare etiology of CS, characterized by functioning adrenal macronodules and variable cortisol secretion.The asymmetric/asynchronous involvement of only one adrenal gland can also occur, making disease diagnosis a challenge.Familial clustering suggests a genetic cause that was recently confirmed, after identification of inactivating germline mutations in armadillo repeat-containing 5 (ARMC5) gene.The insidious nature of this disease and the well-known deleterious effect of hypercortisolism favor genetic study of other family members, to diagnose and treat these patients timely.As ARMC5 is expressed in many organs and recent findings suggest an association of PBMAH and meningioma, a watchful follow-up is required.

ARMC5 Primary Bilateral Macronodular Adrenal Hyperplasia Associated with a Meningioma: A Family Report

“…ARMC5 gene mutations has been identified in a large number of patients and familial cases with PBMAH [ 3 , 6 – 8 , 17 ]. ARMC5 is a cytosolic protein with no enzymatic activity, containing 7 armadillo domains and one BTB domain towards its C-terminus, which allows its dimerization or trimerization [ 20 ].…”

“…Despite the reduced cortisol secretion capacity of each cell, progressive hypercortisolism results from the increased number of adrenocortical cells, explaining the slow and progressive development of Cushing syndrome [ 3 ]. The ARMC5 antiapototic effect is responsible for the growth of bilateral masses [ 2 , 8 , 16 ]. The presence or absence of ARMC5 mutations may be associated with diverse phenotypes [ 16 ].…”

“…The pathophysiological process that leads to PBMAH has not been fully clarified [ 6 – 8 ]. Steroidogenesis has been shown to be relatively inefficient in PBMAH, which explains the indolent natural history of the disease, and the late manifestation of clinical hypercortisolism, present only after severe and irregular enlargement of the adrenal glands [ 2 ].…”

Coexistence of Myelolipoma and Primary Bilateral Macronodular Adrenal Hyperplasia With GIP-Dependent Cushing's Syndrome

“…Recent studies have shown that inactivating mutations of tumor suppressor gene ARMC5 occur in ~25% of apparently sporadic BMAH patients (42–44), and more frequently in familial clustering cases (45, 46). Inactivation of ARMC5 does not appear to be associated with specific aberrant receptor phenotypes in BMAH as cortisol responses to upright posture, metoclopramide, and vasopressin were found in some mutated cases; however so far no patients with GIP-dependent BMAH were found to carry ARMC5 mutation, and this was also the case in our patient (46–48).…”

Caracterização de culturas de células de hiperplasia macronodular adrenal primária (PMAH) como modelo biológico para estudo funcional do gene >i<ARMC5>/i<.

“…De fato, se desconhece a real prevalência da forma familial da doença, uma vez que não é realizada uma avaliação sistemática dos parentes dos pacientes com PMAH. Até a presente data, foram descritas na literatura poucas famílias com a forma herdada da doença (8,19,21,(24)(25)(26).…”