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

2020 ◽  
Vol 2020 ◽  
pp. 1-5
Author(s):  
M. J. Ferreira ◽  
J. Pedro ◽  
D. Salazar ◽  
C. Costa ◽  
J. Aragão Rodrigues ◽  
...  
Keyword(s):  
Clinical Characteristics ◽  
Germline Mutations ◽  
Pathogenic Variant ◽  
Clinical Spectrum ◽  
Genetic Mutations ◽  
Cortisol Secretion ◽  
Adrenal Hyperplasia ◽  
Familial Clustering ◽  
Armadillo Repeat

Primary bilateral adrenal macronodular hyperplasia is characterized by functioning adrenal macronodules and variable cortisol secretion. Familial clustering suggests a genetic cause that has been confirmed with the identification of some genetic mutations, including inactivating germline mutations, in armadillo repeat containing 5 (ARMC5) gene. The identification of the pathogenic variant enables the physician to identify and treat these patients earlier and more effectively. It has also been noticed that patients with germline causative variants show a different clinical spectrum, presenting specific clinical characteristics, as the association with the presence of meningiomas.

scholarly journals PRKACA mutations in cortisol-producing adenomas and adrenal hyperplasia: a single-center study of 60 cases

2015 ◽  
Vol 172 (6) ◽  
pp. 677-685 ◽  
Author(s):  
Anne Thiel ◽  
Anna-Carinna Reis ◽  
Matthias Haase ◽  
Gerald Goh ◽  
Matthias Schott ◽  
...  
Keyword(s):  
Cushing’S Syndrome ◽  
Somatic Mutations ◽  
Germline Mutations ◽  
Cushing's Syndrome ◽  
Cortisol Secretion ◽  
Adrenal Hyperplasia ◽  
Genetic Studies ◽  
Younger Age ◽  
Single Center Study ◽  
Autonomous Cortisol Secretion

ObjectiveCortisol excess due to adrenal adenomas or hyperplasia causes Cushing's syndrome. Recent genetic studies have identified a somatic PRKACAL206R mutation as a cause of cortisol-producing adenomas. We aimed to compare the clinical features of PRKACA-mutant lesions with those of CTNNB1 mutations, and to search for similar mutations in unilateral hyperplasia or tumors co-secreting aldosterone.Design, patients, and methodsIn this study, 60 patients with cortisol excess who had adrenalectomies at our institution between 1992 and 2013 were assessed, and somatic mutations were determined by Sanger sequencing. A total of 36 patients had overt Cushing's syndrome, the remainder were subclinical: 59 cases were adenomas (three bilateral) and one was classified as hyperplasia. Four tumors had proven co-secretion of aldosterone.ResultsAmong cortisol-secreting unilateral lesions without evidence of co-secretion (n=52), we identified somatic mutations in PRKACA (L206R) in 23.1%, CTNNB1 (S45P, S45F) in 23.1%, GNAS (R201C) in 5.8%, and CTNNB1+GNAS (S45P, R201H) in 1.9%. PRKACA and GNAS mutations were mutually exclusive. Of the co-secreting tumors, two (50%) had mutations in KCNJ5 (G151R and L168R). The hyperplastic gland showed a PRKACAL206R mutation, while patients with bilateral adenomas did not have known somatic mutations. PRKACA-mutant lesions were associated with younger age, overt Cushing's syndrome, and higher cortisol levels vs non-PRKACA-mutant or CTNNB1-mutant lesions. CTNNB1 mutations were more significantly associated with right than left lesions.ConclusionsPRKACAL206R is present not only in adenomas, but also in unilateral hyperplasia and is associated with more severe autonomous cortisol secretion. Bilateral adenomas may be caused by yet-unknown germline mutations.

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

2017 ◽  
Vol 2017 ◽  
Author(s):  
Teresa Rego ◽  
Fernando Fonseca ◽  
Stéphanie Espiard ◽  
Karine Perlemoine ◽  
Jérôme Bertherat ◽  
...  
Keyword(s):  
Genetic Study ◽  
Deleterious Effect ◽  
Clinical Signs ◽  
Germline Mutations ◽  
Disease Diagnosis ◽  
Bilateral Adrenalectomy ◽  
List Type ◽  
Free Cortisol ◽  
Familial Clustering ◽  
Armadillo Repeat

Summary PBMAH 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.

Cullin 3 is a partner of Armadillo Repeat Containing 5 (ARMC5), the product of the gene responsible for Primary Bilateral Macronodular Adrenal Hyperplasia

2018 ◽  
Author(s):  
Isadora Cavalcante ◽  
Eric Clauser ◽  
Anna Vaczlavik ◽  
Ludivine Drougat ◽  
Claudimara Lotfi ◽  
...  
Keyword(s):  
Adrenal Hyperplasia ◽  
Cullin 3 ◽  
Armadillo Repeat

scholarly journals The Clinical Characteristics of Congenital Adrenal Hyperplasia

2009 ◽  
Vol 45 (2) ◽  
pp. 105
Author(s):  
Sun Ju Park ◽  
Ji Yeon Seo ◽  
Chan Jong Kim ◽  
Young Jong Woo
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Clinical Characteristics ◽  
Adrenal Hyperplasia

Cullin 3 is a partner of Armadillo repeat containing 5 (ARMC5), the product of the gene responsible for primary bilateral macronodular adrenal hyperplasia

2018 ◽  
Vol 79 (3) ◽  
pp. 184-185
Author(s):  
Isadora P. Cavalcante ◽  
Eric Clauser ◽  
Anna Vaczlavik ◽  
Ludivine Drougat ◽  
Claudimara Lotfi ◽  
...  
Keyword(s):  
Adrenal Hyperplasia ◽  
Cullin 3 ◽  
Armadillo Repeat

Beyond Li-Fraumeni syndrome: Clinical characteristics of families with p53 germline mutations

2008 ◽  
Vol 26 (15_suppl) ◽  
pp. 11031-11031
Author(s):  
K. D. Gonzalez ◽  
K. A. Noltner ◽  
C. H. Buzin ◽  
D. Gu ◽  
C. Y. Wen-Fong ◽  
...  
Keyword(s):  
Clinical Characteristics ◽  
Germline Mutations ◽  
Li Fraumeni Syndrome ◽  
Li Fraumeni

scholarly journals SAT-193 Clinical Case of ARMC5 Tumor Syndrome: A Rare Case of Cushing’s Syndrome from Primary Bilateral Macronodular Adrenal Hyperplasia Caused by ARMC5 Mutation with Concomitant Presence of Meningiomas and Primary Hyperparathyroidism

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Sahil Parikh ◽  
Jeena Matthews ◽  
Sara E Lubitz ◽  
Stephen Schneider
Keyword(s):  
Tumor Suppressor ◽  
Primary Hyperparathyroidism ◽  
Tumor Suppressor Gene ◽  
Cushing’S Syndrome ◽  
Kidney Stones ◽  
Suppressor Gene ◽  
Cushing's Syndrome ◽  
Adrenal Hyperplasia ◽  
History Of ◽  
Armadillo Repeat

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 (&lt;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.

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