Primary bilateral macronodular adrenal hyperplasia

Venanzi, Agostino De; Alencar, Guilherme Asmar; Bourdeau, Isabelle; Fragoso, Maria Candida Barisson Villares; Lacroix, André

doi:10.1097/med.0000000000000061

Cited by 59 publications

(71 citation statements)

References 52 publications

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“…The genetic basis of hereditary BMAH appears to be heterogeneous (12,14,15). A limited number of cases of BMAH were described in association with the multiple endocrine neoplasia type 1 syndrome (14,15) and the hereditary leiomyomatosis and renal cancer syndrome (14,16).…”

Section: Introductionmentioning

confidence: 99%

“…The aberrant stimulation of steroidogenesis can be under the control of ectopic receptors such as those for glucose-dependent insulinotropic peptide, catecholamines (b-adrenergic receptor), vasopressin (V 2 -V 3 -vasopressin receptor), serotonin (5-HT 7 receptor), glucagon, and probably angiotensin II receptor (AT1R). It can also result from increased expression or altered activity of eutopic receptors such as those for vasopressin (V 1 -vasopressin receptor), luteinizing hormone (LH)/human chorionic gonadotropin, serotonin (5-HT 4 receptor), and leptin receptor (11,12). In addition, adrenocorticotropic hormone (ACTH) can be produced in clusters of steroidogenic cells in BMAH tissues and regulate steroidogenesis in a paracrine manner (13).…”

Section: Introductionmentioning

confidence: 99%

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ARMC5 mutations in a large French-Canadian family with cortisol-secreting β-adrenergic/vasopressin responsive bilateral macronodular adrenal hyperplasia

Bourdeau

Oble²,

Magne³

et al. 2016

European Journal of Endocrinology

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Background: Bilateral macronodular adrenal hyperplasia (BMAH) is a rare cause of Cushing's syndrome (CS) and its familial clustering has been described previously. Recent studies identified that ARMC5 mutations occur frequently in BMAH, but the relation between ARMC5 mutation and the expression of aberrant G-protein-coupled receptor has not been examined in detail yet. Methods: We studied a large French-Canadian family with BMAH and sub-clinical or overt CS. Screening was performed using the 1-mg dexamethasone suppression test (DST) in 28 family members. Screening for aberrant regulation of cortisol by various hormone receptors were examined in vivo in nine individuals. Sequencing of the coding regions of ARMC5 gene was carried out. Results: Morning ambulating cortisol post 1 mg DST were O50 nmol/l in 5/8 members in generation II (57-68 years old), 9/22 in generation III (26-46 years old). Adrenal size was enlarged at different degrees. All affected patients increased cortisol following upright posture, insulin-induced hypoglycemia and/or isoproterenol infusion. b-blockers led to the reduction of cortisol secretion in all patients with the exception of two who had adrenalectomies because of b-blockers intolerance. We identified a heterozygous germline variant in the ARMC5 gene c.327_328insC, (p.Ala110Argfs*9) in nine individuals with clinical or subclinical CS, in four out of six individuals with abnormal suppression to dexamethasone at initial investigation and one out of six individuals with current normal clinical screening tests. Conclusions: Systematic screening of members of the same family with hereditary BMAH allows the diagnosis of unsuspected subclinical CS associated with early BMAH. The relation between the causative ARMC5 mutation and the reproducible pattern of aberrant b-adrenergic and V 1 -vasopressin receptors identified in this family remains to be elucidated.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ARMC5 mutations in a large French-Canadian family with cortisol-secreting β-adrenergic/vasopressin responsive bilateral macronodular adrenal hyperplasia

Bourdeau

Oble²,

Magne³

et al. 2016

European Journal of Endocrinology

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“…11–13 However, a variant (c-BMAH; childhood BMAH) associated with McCune-Albright syndrome has been reported, arising in early childhood with more florid Cushing's syndrome presentation 6 11–13. Grossly, the adrenal glands appear enlarged and distorted, with a combined weight of 60–200 g 11 13 16 34. The external surface of the glands is often ‘bosselated’ in appearance.…”

Section: Histopathological Correlates Of Cushing's Syndromementioning

confidence: 99%

“…The external surface of the glands is often ‘bosselated’ in appearance. Cross-section of the gland reveals uncapsulated yellow to golden-yellow nodules ranging from 1 cm to 5 cm with irregular light-brown foci 11 13 16 34. Microscopically, the cells are pale, lipid-rich and contain vacuolated cytoplasm, admixed with rare compact cells containing strong eosinophilic cytoplasm (figure 3B).…”

Section: Histopathological Correlates Of Cushing's Syndromementioning

confidence: 99%

Republished: Clinicopathological correlates of adrenal Cushing's syndrome

Duan

Hernandez

Mete

2015

Postgraduate Medical Journal

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Endogenous Cushing's syndrome is a rare endocrine disorder that incurs significant cardiovascular morbidity and mortality, due to glucocorticoid excess. It comprises adrenal (20%) and non-adrenal (80%) aetiologies. While the majority of cases are attributed to pituitary or ectopic corticotropin (ACTH) overproduction, primary cortisol-producing adrenal cortical lesions are increasingly recognised in the pathophysiology of Cushing's syndrome. Our understanding of this disease has progressed substantially over the past decade. Recently, important mechanisms underlying the pathogenesis of adrenal hypercortisolism have been elucidated with the discovery of mutations in cyclic AMP signalling (PRKACA, PRKAR1A, GNAS, PDE11A, PDE8B), armadillo repeat containing 5 gene (ARMC5) a putative tumour suppressor gene, aberrant G-protein-coupled receptors, and intra-adrenal secretion of ACTH. Accurate subtyping of Cushing's syndrome is crucial for treatment decision-making and requires a complete integration of clinical, biochemical, imaging and pathology findings. Pathological correlates in the adrenal glands include hyperplasia, adenoma and carcinoma. While the most common presentation is diffuse adrenocortical hyperplasia secondary to excess ACTH production, this entity is usually treated with pituitary or ectopic tumour resection. Therefore, when confronted with adrenalectomy specimens in the setting of Cushing's syndrome, surgical pathologists are most commonly exposed to adrenocortical adenomas, carcinomas and primary macronodular or micronodular hyperplasia. This review provides an update on the rapidly evolving knowledge of adrenal Cushing's syndrome and discusses the clinicopathological correlations of this important disease.

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“…In the great majority of cases, ACTH-independent CS is due to cortisol hypersecretion by unilateral adrenocortical adenoma or carcinoma [2]. More rarely, glucocorticoid excess may result from bilateral adrenocortical diseases including both micronodular and macronodular hyperplasia, the latter being now known as bilateral macronodular adrenal hyperplasia (BMAH) [2,3]. Adrenal lesions incidentally found during abdominal CT-scan belong to the most prevalent human tumors since they can be observed in 3-4 % of the general population [4].…”

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Abnormal Sensitivity to Glucagon and Related Peptides in Primary Adrenal Cushing’s Syndrome

et al. 2014

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Illegitimate G-protein coupled receptors are known to control cortisol secretion in adrenal adenomas and bilateral macronodular adrenal hyperplasias (BMAHs) causing Cushing's syndrome. In the present study, we have evaluated the role of glucagon in the regulation of cortisol secretion in 13 patients with BMAH or adrenocortical adenoma causing subclinical or overt Cushing's syndrome. Injection of glucagon provoked an increase in plasma cortisol in 2 patients. After surgery, immunohistochemical studies showed the presence of glucagon receptor-like immunoreactivity in clusters of spongiocytic cells in adrenal tissues from patients who were sensitive in vivo to glucagon. We also observed an in vitro cortisol response to vasoactive intestinal peptide from an adenoma, which was insensitive to glucagon and pituitary adenylate cyclase-activating peptide. Altogether, our data show that ectopic glucagon receptors are expressed in some adrenal cortisol-producing benign lesions. Our results also indicate that circulating glucagon may influence cortisol release under fasting conditions.

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Primary bilateral macronodular adrenal hyperplasia

Cited by 59 publications

References 52 publications

ARMC5 mutations in a large French-Canadian family with cortisol-secreting β-adrenergic/vasopressin responsive bilateral macronodular adrenal hyperplasia

ARMC5 mutations in a large French-Canadian family with cortisol-secreting β-adrenergic/vasopressin responsive bilateral macronodular adrenal hyperplasia

Republished: Clinicopathological correlates of adrenal Cushing's syndrome

Abnormal Sensitivity to Glucagon and Related Peptides in Primary Adrenal Cushing’s Syndrome

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