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International audience; PURPOSE: This study aimed to investigate the genetic cause of food-dependent Cushing syndrome (FDCS) observed in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) and adrenal ectopic expression of the glucose-dependent insulinotropic polypeptide receptor. Germline ARMC5 alterations have been reported in about 25% of PBMAH index cases but are absent in patients with FDCS. METHODS: A multiomics analysis of PBMAH tissues from 36 patients treated by adrenalectomy was performed (RNA sequencing, single-nucleotide variant array, methylome, miRNome, exome sequencing). RESULTS: The integrative analysis revealed 3 molecular groups with different clinical features, namely G1, comprising 16 patients with ARMC5 inactivating variants; G2, comprising 6 patients with FDCS with glucose-dependent insulinotropic polypeptide receptor ectopic expression; and G3, comprising 14 patients with a less severe phenotype. Exome sequencing revealed germline truncating variants of KDM1A in 5 G2 patients, constantly associated with a somatic loss of the KDM1A wild-type allele on 1p, leading to a loss of KDM1A expression both at messenger RNA and protein levels (P = 1.2 × 10(-12) and P < .01, respectively). Subsequently, KDM1A pathogenic variants were identified in 4 of 4 additional index cases with FDCS. CONCLUSION: KDM1A inactivation explains about 90% of FDCS PBMAH. Genetic screening for ARMC5 and KDM1A can now be offered for most PBMAH operated patients and their families, opening the way to earlier diagnosis and improved management.

Introduction: There is an increasing number of adrenal tumours discovered incidentally during imaging examinations performed for many different indications. Based on imaging results, it is possible to differentiate benign from malignant adrenal masses, although there is still a number of equivocal imaging findings. Our study presents 77 cases of adrenal tumours in which imaging was inconclusive and the final diagnosis was stated only after surgery and histopathological examination. Material and methods: Retrospective data analysis: 77 cases of indeterminate adrenal tumours with a presumptive diagnosis of “nonadenoma” in patients operated within a 16-year period (2004–2019). None of the patients had a history of malignancy, and all tumours were hormonally inactive. On contrast-enhanced computed tomography (CT), the native density of all tumours was higher than 10 Hounsfield Units (HU), and the absolute percentage washout (APW) and relative percentage washout (RPW) were lower than 60% and 40%, respectively. Results: The most common findings were adrenal adenoma (25.9%), macronodular adrenal hyperplasia (16.9%), ganglioneuroma (15.6%), and haemorrhage with posthaemorrhagic changes (13%). In total, there were 12 various histopathological diagnoses in this group. There were only 2 (2.6%) malignant (adrenal cancer and leiomyosarcoma) and 3 (3.9%) potentially malignant (pheochromocytoma) lesions in this group. Conclusions: It is often impossible to make a correct diagnosis in a clinical setting until it is histologically verified. “Nonadenoma” adrenal tumours constitute a heterogeneous group including very rare pathologies. The risk of malignancy in indeterminate adrenal tumours is relatively low.

Primary bilateral macronodular adrenal hyperplasia (PBMAH), characterized by bilateral benign adrenal macronodules (>1 cm) potentially responsible for variable levels of cortisol excess, is a rare and heterogeneous disease. However, its frequency increases due to incidentally diagnosed cases on abdominal imaging carried out for reasons other than suspected adrenal disease. Mostly isolated, it can also be associated with dominantly inherited genetic conditions in rare cases. Considering the bilateral nature of adrenal involvement and the description of familial cases, the search of a genetic predisposition has led to the identification of germline heterozygous inactivating mutations of the putative tumor suppressor gene ARMC5, causing around 25% of the apparent sporadic cases. Rigorous biochemical and imaging assessment are key elements in the management of this challenging disease in terms of diagnosis. Treatment is reserved for symptomatic patients with overt or subclinical Cushing syndrome, and was historically based on bilateral adrenalectomy, which nowadays tends to be replaced by unilateral adrenalectomy or lifelong treatment with cortisol synthesis inhibitors.

Although adrenal resection is a major option to control hypercortisolemia in patients with bilateral macronodular adrenal hyperplasia, a predictive method for postoperative cortisol production has not been established. A 53-year-old man with ulcerative colitis was referred to our hospital for bilateral multiple adrenal nodules and hypertension. Physical and endocrinological examination revealed inappropriate cortisol production and suppressed secretion of adrenocorticotropic hormone with no typical signs of Cushing's syndrome. Imaging analysis revealed bilateral adrenal nodular enlargement, the nodules of which had the radiological features of adrenocortical adenomas without inter-nodular heterogeneity. In addition, computed tomography volumetry demonstrated that the left adrenal gland (70 mL) accounts for three quarters of the total adrenal volume (93 mL). The patient was diagnosed as subclinical Cushing's syndrome due to bilateral macronodular adrenal hyperplasia, and subsequently underwent a left laparoscopic adrenalectomy with the estimation of 75% decrease in the cortisol level based on the adrenal volume. The surgical treatment ultimately resulted in control of the cortisol level within the normal range, which was compatible to our preoperative prediction. However, regardless of the sufficient cortisol level, ulcerative colitis was exacerbated after the surgery, which needed a systemic therapy for remission. This case indicates successful surgical control of hypercortisolemia based on computed tomography volumetry in bilateral macronodular adrenal hyperplasia, as well as the perioperative exacerbation risk for inflammatory diseases in Cushing's syndrome. We report the potential utility of computed tomography volumetry as a quantitative method with retrospective evaluation of our historical cases.

Bilateral macronodular adrenal hyperplasia (BMAH) is a rare cause of Cushing’s syndrome. In this case cortisol production can be regulated by both genetic factors and various molecular mechanisms. The presence of aberrant or overexpression of eutopic receptors on the membrane of adrenal cortex may lead to activation of cAMP/PKA signaling pathways and consequently, pathological stimulation of steroidogenesis. Since proving the effectiveness of unilateral adrenalectomy in BMAH by achievement of stable remission, preoperative clinical and laboratory tests (ligand-induced tests) are no longer of relevant. Nevertheless, in the absence of normalization of the level of cortisol in the postoperative period or its recurrence, subsequent specific targeted medical options can be offered only if expression/hyperexpression predominance of one or another receptor. Their detection becomes possible using more reliable diagnostic methods such as polymerase chain reaction (PCR) and immunohistochemical studies (IHC) than clinical laboratory tests. At the moment, PCR has gained a wider application. This article summarizes data on the use of immunohistochemical study in BMAH.

A monoallelic germline alteration of ARMC5 causes primary bilateral macronodular adrenal hyperplasia (PBMAH) with Cushing’s syndrome via its subsequent somatic alteration on the other allele as the second hit. PBMAH is sometimes complicated with meningioma. Dependency of such a multi-organ disease on the second hit mechanism was reported before, but this finding has not been confirmed yet. We describe a case of a 65-year-old female with PBMAH, carrying a heterozygous germline alteration of ARMC5, p.R267*, complicated with meningioma associated with somatic loss of heterozygosity (LOH) of the unaffected allele. Pathogenic alterations of ARMC5 may also contribute to the development of meningioma by the two-hit mechanism.

Summary Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of ACTH-independent Cushing syndrome (CS). This condition is characterized by glucocorticoid and/or mineralocorticoid excess, and is commonly regulated by aberrant G-protein coupled receptor expression may be subclinical, allowing the disease to progress for years undetected. Inhibin A is a glycoprotein hormone and tumor marker produced by certain endocrine glands including the adrenal cortex, which has not been previously investigated as a potential tumor marker for PBMAH. In the present report, serum inhibin A levels were evaluated in three patients with PBMAH before and after adrenalectomy. In all cases, serum inhibin A was elevated preoperatively and subsequently fell within the normal range after adrenalectomy. Additionally, adrenal tissues stained positive for inhibin A. We conclude that serum inhibin A levels may be a potential tumor marker for PBMAH. Learning points: PBMAH is a rare cause of CS. PBMAH may have an insidious presentation, allowing the disease to progress for years prior to diagnosis. Inhibin A is a heterodimeric glycoprotein hormone expressed in the gonads and adrenal cortex. Inhibin A serum concentrations are elevated in some patients with PBMAH, suggesting the potential use of this hormone as a tumor marker. Further exploration of serum inhibin A concentration, as it relates to PBMAH disease progression, is warranted to determine if this hormone could serve as an early detection marker and/or predictor of successful surgical treatment.

Bilateral hyperplasias of the adrenal cortex are rare causes of chronic endogenous hypercortisolemia also called Cushing syndrome. These hyperplasias have been classified in two categories based on the adrenal nodule size: the micronodular types include Primary Pigmented Nodular Adrenocortical Disease (PPNAD) and isolated Micronodular Adrenal Disease (iMAD) and the macronodular also named Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH). This review discusses the genetic and molecular causes of these different forms of hyperplasia that involve mutations and dysregulation of various regulators of the cAMP/protein kinase A (PKA) pathway. PKA signaling is the main pathway controlling cortisol secretion in adrenocortical cells under ACTH stimulation. Although mutations of the regulatory subunit R1α of PKA (PRKAR1A) is the main cause of familial and sporadic PPNAD, inactivation of two cAMP-binding phosphodiesterases (PDE11A and PDE8B) are associated with iMAD even if they are also found in PPNAD and PBMAH cases. Interestingly, PBMAH that is observed in multiple familial syndrome such as APC, menin, fumarate hydratase genes, has initially been associated with the aberrant expression of G-protein coupled receptors (GPCR) leading to an activation of cAMP/PKA pathway. However, more recently, the discovery of germline mutations in Armadillo repeat containing protein 5 (ARMC5) gene in 25–50% of PBMAH patients highlights its importance in the development of PBMAH. The potential relationship between ARMC5 mutations and aberrant GPCR expression is discussed as well as the potential other causes of PBMAH.

Cushing’s syndrome is the set of clinical manifestations secondary to a chronic excess of glucocorticoids. Bilateral macronodular adrenal hyperplasia with subclinical cortisol secretion is the most common, but its prevalence remains unknown. We describe a case of bilateral macronodular adrenal hyperplasia. This is a 36-year-old female patient who had been consulting for secondary amenorrhea and developing asthenia for 4 months. The clinical examination noted an overweight patient with high blood pressure, facio-trunk obesity, hirsutism and purple stretch marks in the abdomen and thighs. Biologically, hypokalemia at 2.9 meq/l (3.5 - 5.4), normal calcemia at 90 mg/l (85 - 104), fasting blood sugar was 0.84 g/l (0.7 - 1), the tests for minute, low and high dexamethasone suppression test revealed insufficient suppression of cortisol. The cortisoluria collected from the second day to the third day of the high dexamethasone suppression test was at 186 μg/24 h (

Summary Mifepristone is a promising option for the management of hypercortisolism associated with hyperglycemia. However, its use may result in serious electrolyte imbalances, especially during dose escalation. In our patient with adrenocorticotropic hormone-independent macro-nodular adrenal hyperplasia, unilateral adrenalectomy resulted in biochemical and clinical improvement, but subclinical hypercortisolism persisted following adrenalectomy. She was started on mifepristone. Unfortunately, she missed her follow-up appointments following dosage escalation and required hospitalization at an intensive care level for severe refractory hypokalemia. Learning points: Mifepristone, a potent antagonist of glucocorticoid receptors, has a high risk of adrenal insufficiency, despite high cortisol levels. Mifepristone is associated with hypokalemia due to spill-over effect of cortisol on unopposed mineralocorticoid receptors. Given the lack of a biochemical parameter to assess improvement, the dosing of mifepristone is based on clinical progress. Patients on mifepristone require anticipation of toxicity, especially when the dose is escalated. The half-life of mifepristone is 85 h, requiring prolonged monitoring for toxicity, even after the medication is held.

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a highly heterogeneous entity. The incidental identification of an increasing number of cases has shifted its clinical expression from the rarely encountered severe forms, regarding both cortisol excess and adrenal enlargement, to mild forms of asymptomatic or oligosymptomatic cases with less impressive imaging phenotypes. Activation of cAMP/PKA pathway, either due to alterations of the different downstream signaling pathways or through aberrantly expressed G-protein-coupled receptors, relates to both cortisol secretion and adrenal growth. Germline ARMC5 mutations are a frequent genetic defect. The diagnostic approach consists of both imaging and hormonal characterization. Imaging characterization should be done separately for each lesion. Endocrine evaluation in cases with clinically overt Cushing’s syndrome (CS) is similar to that applied for all forms of CS. In incidentally detected PBMAH, hormonal evaluation includes testing for primary aldosteronism, pheochromocytoma and evaluation for autonomous cortisol secretion, using the 1 mg overnight dexamethasone suppression test. Midnight cortisol or 24-h urinary free cortisol may aid in establishing the degree of cortisol excess. In patients with hypercortisolism, ACTH levels should be measured in order to establish ACTH independency. At variance with other forms of CS, PBMAH may be characterized by a distinct pattern of inefficient steroidogenesis. The appropriate management of PBMAH remains controversial. Bilateral adrenalectomy results in lifetime steroid dependency and is better reserved only for patients with severe CS. Unilateral adrenalectomy might be considered in selected patients. In cases where the regulation of cortisol secretion is mediated by aberrant receptors there is some potential for medical therapy.

The aim of this review is to analyze the benefits and potential drawbacks of unilateral adrenalectomy (UA) for the treatment of patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) and hypercortisolism with either overt or subclinical Cushing's syndrome (CS). UA has progressively emerged as an interesting treatment for PBMAH as it offers a high rate of remission of CS, even in patients with free urinary cortisol well above 2 times the upper limit of normal. UA carries a risk for secondary adrenal insufficiency, which cannot be properly identified by the cosyntropin test but is both limited and transient. This makes it an attractive alternative to bilateral adrenalectomy (BA), which condemns the patient to total and definitive primary adrenal insufficiency and a risk for adrenal crisis. Recently, however, the issue has been raised of a potential risk of mortality in UA patients, linked to persistent dysregulated secretion of cortisol or recurrence. Further studies are necessary to better compare the long-term risks of dysregulated secretion of cortisol with UA vs adrenal insufficiency in BA. Up to now, the clinician has to remember that UA can be transformed in BA, whereas the opposite is impossible

Objective To investigate the validity of discharge ICD-10 codes in detecting the etiology of endogenous Cushing’s syndrome (CS) in hospitalized patients. Methods We evaluated the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of CS etiology-related ICD-10 codes or code combinations by comparing hospital discharge administrative data (DAD) with established diagnoses from medical records. Results Coding for patients with adrenocortical adenoma (ACA) and those with bilateral macronodular adrenal hyperplasia (BMAH) demonstrated disappointingly low sensitivity at 78.8% (95% CI: 70.1–85.6%) and 83.9% (95% CI: 65.5–93.9%), respectively. BMAH had the lowest PPV of 74.3% (95% CI: 56.4–86.9%). In confirmed ACA patients, the sensitivity for ACA code combinations was higher in patients initially admitted to the Department of Endocrinology before surgery than that in patients directly admitted to the Department of Urology (90.0 vs 73.1%, P = 0.033). The same phenomenon was observed in the PPV for the BMAH code (100.0 vs 60.9%, P = 0.012). Misinterpreted or confusing situations caused by coders (68.1%) and by the omission or denormalized documentation of symptomatic diagnosis by clinicians (26.1%) accounted for the main source of coding errors. Conclusions Hospital DAD is an effective data source for evaluating the etiology of CS but not ACA and BMAH. Improving surgeons’ documentation, especially in the delineation of symptomatic and locative diagnoses in discharge abstracts; department- or disease-specific training for coders and more multidisciplinary collaboration are ways to enhance the applicability of administrative data for CS etiologies.

Aberrant cortisol secretion responses after exogenous stimuli such as upright posture, eating a mixed meal or receiving agents influencing aberrant G-protein-coupled receptors in adrenal glands, are often observed in patients with bilateral macronodular adrenal hyperplasia (BMAH). However, little is known about whether this aberrant response is retained after unilateral adrenalectomy. Here, we describe a 61-year-old postmenopausal Japanese woman with unsatisfactorily controlled hypertension who was referred to us for further investigation due to her pre-obesity characteristics (body mass index 28.4 kg/m2). Cushing's signs and serum cortisol at 16.2 µg/dL with undetectable adrenocorticotropic hormone indicated adrenal Cushing's syndrome. Adrenal imaging revealed bilaterally enlarged adrenal glands with 131-I adosterol uptake; hence, BMAH was diagnosed. Preoperatively, in vivo screening for aberrant adrenal receptors revealed an aberrant response of cortisol secretion on metoclopramide challenge. The patient underwent unilateral adrenalectomy; thereafter, glucocorticoid replacement therapy was reduced to hydrocortisone 15 mg/day at postoperative day 6. Fasting morning serum cortisol level measured at postoperative day 8 was 2.96 µg/dL, suggesting adrenal insufficiency. However, following metoclopramide administration serum cortisol level rose to 19.7 µg/dL, indicating potential efficient adrenal function. Aberrant cortisol secretory capacity was thus preserved in BMAH, even in a state of adrenal insufficiency after unilateral adrenalectomy. Caution should be exercised when assessing the hypothalamus-pituitary-adrenal axis, because in this patient, a high cortisol level did not guarantee appropriate adrenal function when the patient was challenged by exogenous stimuli.

Context: The literature on outcomes of bilateral adrenalectomy (BADx) in Cushing's syndrome (CS) is scant. Aims: The aim of this study is to analyze the short- and long-term outcomes of patients who underwent BADx and to compare the outcomes among different etiologies of CS. Settings and Design: This is a retrospective analysis of patients who underwent BADx for CS at our center between 2005 and 2018. Materials and Methods: In all, 33 patients were studied for clinical outcomes, survival rates, and long-term complications. Statistical Analysis: All analyses were performed with SPSS software (version 21.0). Results: The mean age at surgery was 39.33 ± 15.67 years. The primary etiology for CS was Cushing's disease (CD) in 42.42%, ectopic source in 36.36%, primary pigmented nodular adrenocortical disease (PPNAD) in 12.12%, and adrenocorticotrophin hormone–independent macronodular adrenal hyperplasia (AIMAH) in 9.09% of patients. The median follow-up time was 72.77 months. Improvement in hypertension and diabetes status after surgery was seen in 78% and 76.19% of patients, respectively. Proximal myopathy improved in 68% of patients. Nelson's syndrome and adrenal crisis were seen in 21.4% of patients each on long-term follow-up. Total mortality after BADx was 33.3%. Mortality in the first 30 days after surgery was seen in five patients (15.15%). Higher cortisol levels at presentation and age more than 40 years were predictors of mortality. Among the Cushing's subtypes, PPNAD had the best prognosis followed by CD. Perioperative Infections were a major cause of mortality. Conclusion: BADx is an effective treatment for CS especially in patients with PPNAD and CD but carries a significant mortality rate too.

L´hyperplasie macronodulaire bilatérale des surrénales (HMBS) est une cause rare de syndrome de Cushing d´origine surrénalienne, représentant moins de 1% des cas. Nous rapportons le cas d´un patient âgé de 48 ans, diabétique et hypertendu. Présentant un syndrome de Cushing clinique. Le bilan étiologique a permis de retenir le diagnostic d´hypercorticisme «Adrenocorticotropic hormone» (ACTH) indépendant en rapport avec une HMBS. Le choix thérapeutique était en faveur d´une surrénalectomie unilatérale gauche orientée par la scintigraphie au noriodocholestérol, avec une bonne évolution. Cependant, vu le risque de récidive et de complications cardiovasculaires, une surveillance au long cours a été programmée.

Bilateral macronodular adrenal hyperplasia (BMAH) is rare cause of Cushing syndrome characterized by enlarged adrenal gland containing multiple nodule which is greater than 10 mm and can reach 30-40 mm. Recently many study suggest that hypercortisolism in BMAH is due to the expression of ectopic horrmone receptor like gastric inhibitory polypeptide, vasopressin, catecholamine or overexpression of eutopic receptor on adrenal glands. Also genetic studies showed that BMAH caused by several somatic gene mutation during the embryogenesis and inherited germline mutation. We report 54 years old man who has Cushing syndrome due to BMAH with a negative response to aberrant hormone receptor test. We performed laparoscopic bilateral adrenalectomy. Both leg edema disappeared and serum cortisol level became to normal after the operation.

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is characterized by bilateral multiple adrenal macro-nodules that often cause mild over-secretion of cortisol in the form of subclinical Cushing’s syndrome. We herein describe a case, wherein unilateral adrenalectomy partially improved hyperglycemia in a patient with PBMAH and suggest the usefulness and limitations of this surgical strategy. A 64-year-old woman with type 2 diabetes had an incidental diagnosis of bilateral adrenal lesions. She had a family history of type 2 diabetes, and her HbA1c level was 8.9% under insulin therapy. She did not present with any symptoms associated with Cushing’s syndrome. The basal cortisol level was in the normal range (12.0 μg/dL); however, the adrenocorticotropic hormone (ACTH) level was suppressed (2.1 pg/mL) and the serum cortisol level was not suppressed in the dexamethasone test. Computed tomography and magnetic resonance imaging showed bilateral adrenal macro-nodules and (131)I-adosterol accumulated in the bilateral adrenal lesions. Collectively, she was diagnosed with subclinical Cushing’s syndrome due to PBMAH complicated with diabetes mellitus, hypertension, and dyslipidemia. Laparoscopic left adrenalectomy was performed, and the pathologic findings were consistent with PBMAH. After unilateral adrenalectomy, serum cortisol levels decreased, and hypertension improved. Both HbA1c levels and insulin requirement also decreased, but insulin therapy was continuously needed. It should be noted that hyperglycemia may not be cured after successful surgery in a patient with PBMAH. Additional operation or medical therapy should be considered if unilateral adrenalectomy is unable to correct hypercortisolism in PBMAH patients.

Most adrenal incidentalomas are non-functioning adenomas that require no treatment. The presence of a myelolipomatous component of adrenal incidentalomas is a rare, but well-known occurrence in both hyperplastic and neoplastic lesions of the adrenal cortex. Although the improvements in abdominal imaging have increased identification of myelolipomatous adrenal cortical adenomas radiologically, due to the rarity of this lesion, the clinical pathological features of these lesions are unclear and can sometimes cause diagnostic difficulty. Eleven patients had surgeries at The University of Texas MD Anderson Cancer Center. Four additional cases were provided from an external collaborator. Of the 15 cases, there were 5 male and 10 female patients, with a median age of 52 years (mean 54 years, range 28-84 years). Clinical presentation included adrenal incidentaloma (n = 9), Cushing syndrome (n = 4, including 1 as a part of Carney complex), and subclinical Cushing syndrome (n = 2, including 1 with bilateral macronodular adrenal hyperplasia). In this study, we present the clinicopathologic features of fifteen myelolipomatous adrenal adenomas, the largest series published thus far.

The genetic alterations that cause the development of glucocorticoid and/or mineralocorticoid producing benign adrenocortical tumors and hyperplasias have largely been elucidated over the past two decades through advances in genomics. In benign aldosterone-producing adrenocortical tumors and hyperplasias, alteration of intracellular calcium signaling has been found to be significant in aldosterone hypersecretion, with causative defects including those in KCNJ5, ATP1A1, ATP2B3, CACNA1D, CACNA1H, and CLCN2. In benign cortisol-producing adrenocortical tumors and hyperplasias abnormal cyclic adenosine monophosphate-protein kinase A signaling has been found to play a central role in tumorigenesis, with pathogenic variants in GNAS, PRKAR1A, PRKACA, PRKACB, PDE11A, and PDE8B being implicated. The role of this signaling pathway in the development of Cushing’s syndrome and adrenocortical tumors was initially discovered through the study of the underlying genetic defects causing the rare multiple endocrine neoplasia syndromes McCune-Albright syndrome and Carney complex with subsequent identification of defects in genes affecting the cyclic adenosine monophosphate-protein kinase A pathway in sporadic tumors. Additionally, germline pathogenic variants in ARMC5, a putative tumor suppressor, were found to be a cause of cortisol-producing primary bilateral macronodular adrenal hyperplasia. This review describes the genetic causes of benign cortisol- and aldosterone-producing adrenocortical tumors.

Primary bilateral adrenocortical hyperplasias are rare forms of pituitary ACTH-independent Cushing's syndrome (CS). They are divided between primary bilateral macronodular adrenal hyperplasia (PBMAH) and micronodular adrenal hyperplasia (MiBAH), which is subdivided in primary pigmented nodular adrenocortical disease (PPNAD) and isolated micronodular adrenocortical disease (i-MAD). One of the most debated aspects surrounding these entities is their most appropriate therapy. Although bilateral adrenalectomy (BA) has previously been the most utilized therapy for patients with overt CS, recent studies have indicated that unilateral adrenalectomy (UA) can be effective in patients with PBMAH and some with MiBAH with fewer long-term side effects. Medical therapies can also be used for bridging to surgery or rarely in the long-term for these patients. We review the various degrees of CS resulting from PBMAH and MiBAH, with a special focus on their respective therapies including UA, taking into account the recent pathophysiological and genetics findings.

Summary Background GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome is caused by aberrant expression of the GIP receptor in adrenal lesions. The bilateral nature of this disease suggests germline genetic predisposition. We aimed to identify the genetic driver event responsible for GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome. Methods We conducted a multicentre, retrospective, cohort study at endocrine hospitals and university hospitals in France, Canada, Italy, Greece, Belgium, and the Netherlands. We collected blood and adrenal samples from patients who had undergone unilateral or bilateral adrenalectomy for GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome. Adrenal samples from patients with primary bilateral macronodular adrenal hyperplasia who had undergone an adrenalectomy for overt or mild Cushing's syndrome without evidence of food-dependent cortisol production and those with GIP-dependent unilateral adrenocortical adenomas were used as control groups. We performed whole genome, whole exome, and targeted next generation sequencing, and copy number analyses of blood and adrenal DNA from patients with familial or sporadic disease. We performed RNA sequencing on adrenal samples and functional analyses of the identified genetic defect in the human adrenocortical cell line H295R. Findings 17 patients with GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome were studied. The median age of patients was 43·3 (95% CI 38·8–47·8) years and most patients (15 [88%]) were women. We identified germline heterozygous pathogenic or most likely pathogenic variants in the KDM1A gene in all 17 patients. We also identified a recurrent deletion in the short p arm of chromosome 1 harboring the KDM1A locus in adrenal lesions of these patients. None of the 29 patients in the control groups had KDM1A germline or somatic alterations. Concomitant genetic inactivation of both KDM1A alleles resulted in loss of KDM1A expression in adrenal lesions. Global gene expression analysis showed GIP receptor upregulation with a log2 fold change of 7·99 (95% CI 7·34–8·66; p=4·4 × 10−125), and differential regulation of several other G protein-coupled receptors in GIP-dependent primary bilateral macronodular hyperplasia samples compared with control samples. In vitro pharmacological inhibition and inactivation of KDM1A by CRISPR-Cas9 genome editing resulted in an increase of GIP receptor transcripts and protein in human adrenocortical H295R cells. Interpretation We propose that GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome results from a two-hit inactivation of KDM1A, consistent with the tumour suppressor gene model of tumorigenesis. Genetic testing and counselling should be offered to these patients and their relatives. Funding Agence Nationale de la Recherche, Fondation du Grand defi Pierre Lavoie, and the French National Cancer Institute.

Bilateral macronodular adrenal hyperplasia (BMAH) is a rare cause of adrenal Cushing's syndrome, accounting for less than 1% of cases. We here report the case of a 48-year-old patient with diabetes and hypertension presenting with clinical signs of Cushing's syndrome. Etiological assessment enabled clinicians to retain the diagnosis of Adrenocorticotropic hormone (ACTH)-independent hypercortisolism associated with BMAH. Unilateral left adrenalectomy was performed based on noriodocholesterol scintigraphy results, with good outcome. However, given the risk of recurrence and cardiovascular complications, long-term monitoring was scheduled.

Purpose: To investigate the genetic cause of Food-dependent Cushing’s syndrome (FDCS) observed in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) and adrenal ectopic expression of the GIP receptor (GIPR). Germline ARMC5 alterations have been reported in about 25 % of PBMAH index cases but are absent in patients with FDCS. Methods: A multi-omics analysis of PBMAH tissues from 36 patients treated by adrenalectomy was performed (RNAseq, SNP array, methylome, miRNome, exome sequencing). Results: The integrative analysis revealed three molecular groups with different clinical features: G1, PBMAH due to ARMC5 inactivating variants; G2, with GIPR ectopic expression and FDCS; and G3, with a less severe phenotype. Exome sequencing revealed germline truncating variants of LSD1/KDM1A in the G2 group, constantly associated with a somatic loss of the LSD1/KDM1A wildtype allele on 1p, leading to a loss of LSD1/KDM1A expression both at mRNA and protein levels (p=1.2x10-12 and p

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.

This review reports the main molecular alterations leading to development of benign cortisol- and/or aldosterone-secreting adrenal tumors. Causes of adrenal Cushing syndrome can be divided in 2 groups: multiple bilateral tumors or adenomas secreting cortisol. Bilateral causes are mainly primary pigmented nodular adrenocortical disease, most of the time due to PRKAR1A germline-inactivating mutations, and primary bilateral macronodular adrenal hyperplasia that can be caused in some rare syndromic cases by germline-inactivating mutations of MEN1, APC, and FH and of ARMC5 in isolated forms. PRKACA somatic-activating mutations are the main alterations in unilateral cortisol-producing adenomas. In primary hyperaldosteronism (PA), familial forms were identified in 1% to 5% of cases: familial hyperaldosteronism type I (FH-I) due to a chimeric CYP11B1/CYP11B2 hybrid gene, FH-II due to CLCN-2 germline mutations, FH-III due to KCNJ5 germline mutations, FH-IV due to CACNA1H germline mutations and PA, and seizures and neurological abnormalities syndrome due to CACNA1D germline mutations. Several somatic mutations have been found in aldosterone-producing adenomas in KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1 genes. In addition to these genetic alterations, genome-wide approaches identified several new alterations in transcriptome, methylome, and miRnome studies, highlighting new pathways involved in steroid dysregulation.

Context. Approximately 50% of familial cases of primary bilateral macronodular adrenal hyperplasia (PBMAH) are caused by mutations in the ARMC5 gene. Case report. We report the case of a 37 year-old patient of Haitian origin, who presented with resistant hypertension. His workup showed high aldosterone (410 pmol/L) with suppressed renin levels (0.2 ng/mL/h) with an aldosterone to renin ratio (ARR) of 2050. Patient also had suppressed ACTH levels ( Genetic analyses. Following genetic counselling, MEN1 gene analysis was performed using sequencing/MLPA techniques but did not reveal a mutation. Initial genetic testing included ARMC5 gene analysis using direct Sanger sequencing which was negative. However, using Next-Generation Sequencing (NGS) and MLPA analysis, a heterozygous germline ARMC5 deletion of exons 5-8 was identified. The deletion is predicted to prematurely truncate the protein product and cause loss of function. The ARMC5 deletion segregated with the disease in his 24 yo son who had bilateral adrenal adenomas that appeared to be non-functional. The patient’s father was also known for having bilateral adrenal masses and hypertension. To our knowledge we report the second case of ARMC5 deletion in familial PBMAH. Suzuki et al. reported two patients, a mother and her son, carrying ARMC5 deletion of exons1-5 and interestingly they were also affected by PBMAH co-secreting cortisol and aldosterone (1). As in this case report, the ARMC5 deletion was missed using Sanger sequencing initially. Conclusion. These cases demonstrate that large deletions may be missed by Sanger sequencing and that the real prevalence of ARMC5 mutations may have been underestimated. The link between deletion of ARMC5 and correlation with PBMAH co-secreting aldosterone and cortisol remains to be determined but may be a step forward for genotype-phenotype correlation. 1.Suzuki S, et al. Endocrine practice: official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2015;21 (10):1152-60.

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 (

Objectives: Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare condition of Cushing’s syndrome (CS) characterized by benign bilateral enlarged adrenal masses. The aim of this study is to analyze clinical features, individualized treatment and prognosis of PBMAH. Methods: Clinical data of 46 patients with PBMAH were retrospectively analyzed compared with 205 patients with unilateral adrenal cortisol-secreting adenoma (UAA), including general information, cortisol evaluations, treatments and prognosis. Results: PBMAH were more frequently found in male, the average age at diagnosis was (52.1±8.7) years; most patients visited hospital due to incidentally findings of bilateral adrenal lesions; had a higher proportion of subclinical CS. The PBMAH cases showed significantly lower levels of basal cortisol, LDDST suppressed cortisol, and HDDST suppressed cortisol than the UAA cases (452.6 ± 183.3 vs. 578.7 ± 166.4 nmol/L, P = 0.003; 394.5 ± 298.9 vs. 549.2 ± 217.7 nmol/L, P= 0.002; 397.3 ± 282.3 vs. 544.3 ± 187.6 nmol/L, P =0.003). Similarly, the PBMAH cases had significantly lower levels of basal 24-h UFC, LDDST suppressed 24-h UFC, and HDDST suppressed 24-h UFC than the UAA patients (1144.4 ± 1048.1 vs. 1674.9 ± 1520.4 nmol/24h, P = 0.032; 1157.3 ± 1483.5 vs. 1940.1 ± 1360.9 nmol/24h, P = 0.003; 1256.4 ± 1767.0 vs. 1969.9 ± 1361.7 nmol/24h, P = 0.011). Compared PBMAH group with UAA group, there were statistically significant differences in the percentage change of cortisol (absolute value after suppressed over the basal value) during LDDST (73.01% ± 39.33% vs. 96.13% ± 31.59%, P =0.001) and during HDDST (73.90% ± 38.53% vs. 96.58% ± 28.79%, P=0.001); and there were statistically significant differences in the percentage change of 24-h UFC during LDDST (90.11% ± 79.60% vs. 134.47% ± 131.26%,P =0.045) and during HDDST (100.05% ± 89.59% vs. 143.75% ± 98.12%, P =0.017). The 24-hour continuous plasma ACTH and cortisol monitoring directly and thoroughly revealed the heterogeneity of hormone secretion of PBMAH cases. Among the 18 PBMAH cases with subclinical CS, 11 only received drug symptomatic treatment; 6 underwent unilateral adrenalectomy on the larger side; 1 not relieved well after unilateral adrenalectomy, then received resection of the contra-side. Among the 28 PBMAH cases with CS, 6 refused surgery because of economic reasons and just received symptomatic drugs treatment with bad prognosis; 15 underwent unilateral adrenalectomy on the larger side; 7 not relieved well after unilateral adrenalectomy, then conducted resection of the contra-side, and at last treated with glucocorticoid replacement obtained good prognosis. Conclusions: PBMAH is often associated with a relatively low degree of cortisol autonomous secretion. It is necessary to choose a specific therapy plan to alleviate the high cortisol state according to the individualized hypercortisolemia condition.

The last 10 years have produced an amazing number of significant discoveries in the field of adrenal endocrinology. The development of the adrenal gland was linked to specific molecules. Cortisol-producing lesions were associated mostly with defects of the cyclic AMP (cAMP) signaling pathway, whereas aldosterone-producing lesions were found to be the result of defects in aldosterone biosynthesis or the potassium channel KCNJ5 and related molecules. Macronodular adrenal hyperplasia was linked to ARMC5 defects and new genes were found to be involved in adrenocortical cancer (ACC). The succinate dehydrogenase (SDH) enzyme was proven to be the most important molecular pathway involved in pheochromocytomas, along with several other genes. Adrenomedullary tumors are now largely molecularly elucidated. Unfortunately, most of these important discoveries have yet to produce new therapeutic tools for our patients with adrenal diseases: ACC in its advanced stages remains largely an untreatable disorder and malignant pheochromocytomas are equally hard to treat. Thus, the challenge for the next 10 years is to translate the important discoveries of the previous decade into substantial advances in the treatment of adrenal disorders and tumors.

Management of patients with bilateral adrenal masses and ACTH-independent Cushing’s syndrome (AICS) is challenging, as bilateral adrenalectomy can lead to steroid dependence and lifelong risk of adrenal crisis. Adrenal venous sampling (AVS) has been previously reported to facilitate lateralization for guiding adrenalectomy. The aim of the current study was to investigate the utility of AVS using protocol from study by Young et al. in the management of patients with bilateral adrenal masses and AICS. A retrospective review of all patients with bilateral adrenal masses and AICS who underwent AVS from 2008 to 2016 was performed. AVS for cortisol and epinephrine was performed with dexamethasone suppression. The adrenal vein to peripheral vein cortisol ratios and side-to-side cortisol lateralization ratios were calculated. AVS was successful in 8 of 9 patients. All 8 patients had AVS results indicating bilateral cortisol hypersecretion. Six patients underwent adrenalectomy: 3 had unilateral adrenalectomy of the larger size mass, 2 had bilateral adrenalectomy (both sides >4 cm.) and 1 had stepwise bilateral adrenalectomy. Final pathology revealed macronodular adrenal hyperplasia in all 6 patients that underwent surgery. AVS was useful in excluding a unilateral adenoma as the source of AICS in this study of patients with bilateral adrenal masses and AICS. However, adrenal mass size influenced surgical decision making more than AVS results. More data are needed before AVS can be advocated as essential for management of patients with bilateral adrenal masses and AICS.

Objectives Primary bilateral macronodular adrenal hyperplasia is an uncommon cause of endogenous Cushing's syndrome characterized by the presence of aberrant adrenal expression of ectopic receptors that regulate steroidogenesis by mimicking the events triggered by ACTH receptor activation. Receptors of this type have been described for several hormones. The aim of the study is to detect these receptors in two patients with ACTH-independent hypercortisolism by means of the application of a screening protocol. Design and methods A protocolized study of aberrant receptors was performed including measurements of ACTH, cortisol and other steroids and hormones. Upright posture test, mixed food and administration of Gonadotropin-Releasing Hormone (GnRH) were used as stimuli. In both patients, a stimulation test with intravenous ACTH was conducted to determinate the cortical response capacity. The study was carried out in three separate days. Results The first patient, who had a hypergonadotropic hypogonadism , presented anomalous cortisol response to the GnRH stimulation, with potential medical treatment by the use of exogenous testosterone . In the second case, the patient with clinical Cushing's syndrome presented anomalous cortisol response to standing, whose potential medical treatment would be the use of beta-blockers . Conclusions This etiological variant of ACTH-independent Cushing's syndrome leads to the use of specific pharmacologic therapies in some cases as alternatives to adrenalectomy . The studied cases show the importance of having a high degree of suspicion when diagnosing less frequent types of Cushing's syndrome.

The investigation and management of unilateral adrenal incidentalomas have been extensively considered in the last decades. While bilateral adrenal incidentalomas represent about 15% of adrenal incidentalomas (AIs), they have been less frequently discussed. The differential diagnosis of bilateral incidentalomas includes metastasis, primary bilateral macronodular adrenal hyperplasia and bilateral cortical adenomas. Less frequent etiologies are bilateral pheochromocytomas, congenital adrenal hyperplasia (CAH), Cushing’s disease or ectopic ACTH secretion with secondary bilateral adrenal hyperplasia, primary malignancies, myelolipomas, infections or hemorrhage. The investigation of bilateral incidentalomas includes the same hormonal evaluation to exclude excess hormone secretion as recommended in unilateral AI, but diagnosis of CAH and adrenal insufficiency should also be excluded. This review is focused on the differential diagnosis, investigation and treatment of bilateral AIs.

OBJECTIVE Osteoporotic fractures associated with Cushing's syndrome (CS) may occur despite normal bone mineral density (BMD). Few studies have described alterations in vertebral microarchitecture in glucocorticoid-treated patients and during CS. Trabecular bone score (TBS) estimates trabecular microarchitecture from dual-energy X-ray absorptiometry acquisitions. Our aim was to compare vertebral BMD and TBS in patients with overt CS and mild autonomous cortisol secretion (MACE), and following cure of overt CS. SETTING University Hospital. DESIGN Monocentric retrospective cross-sectional and longitudinal studies of consecutive patients. PATIENTS A total of 110 patients were studied: 53 patients had CS (35, 11 and 7 patients with Cushing's disease, bilateral macronodular adrenal hyperplasia and ectopic ACTH secretion respectively); 39 patients had MACE (10 patients with a late post-operative recurrence of Cushing's disease and 29 patients with adrenal incidentalomas); 18 patients with non-secreting adrenal incidentalomas. 14 patients with overt CS were followed for up to 2 years after cure. RESULTS Vertebral osteoporosis at BMD and degraded microarchitecture at TBS were found in 24% and 43% of patients with CS, respectively (P

Management of ACTH-independent CS in the setting of B/L adrenal masses can be challenging. We present a patient with concomitant cortisol and aldosterone hypersecretion and B/L adrenal masses who was treated with unilateral adrenalectomy (UA) based on simultaneous B/L adrenal vein sampling (AVS) results normalized to plasma epinephrine levels, to correct for flow and dilution. A 60-year-old lady presented for evaluation of incidentally discovered B/L adrenal masses. CT abdomen with contrast revealed B/L lobulated adrenal glands measuring 3.4 x 5.5 x 4.1 cm on the right and 3.8 x 4.2 x 2 cm on the left (pre contrast density of 37 and 44 Hounsfield Units respectively). She had a recent diagnosis of HTN and prediabetes. She reported fatigue, easy bruising, and muscle weakness. Family history was notable for a sister with CS and B/L adrenal masses who was successfully treated with UA. On physical examination her BP was 160/94 mm Hg and she did not have an obvious cushingoid appearance. Laboratory testing included an elevated AM serum cortisol level of 16.6 mcg/dL following 1 mg of dexamethasone given at 11 pm the previous night. ACTH was 6.5) consistent with cortisol hypersecretion. The right to left cortisol ratio was 2.3 (>/= 2.3), consistent with right sided predominance. Right to left ratio of the epinephrine corrected cortisol level was 2.7. She underwent right adrenalectomy, and pathology showed macronodular adrenal hyperplasia. Postoperatively, she had resolution of HTN and normalization of 24 hour urine free cortisol. UA is increasingly becoming recognized as a successful treatment for BMAH due to lower risk of adrenal crisis when compared to B/L adrenalectomy. In a recent publication, remission from CS was seen in 94.4 % of patients with BMAH following UA, with recurrence in 19% of patients. The mean time to recurrence was 5 years. We utilized cutoff values that were previously reported for cortisol lateralization in interpreting AVS. Our patient attained remission of CS 9 months post UA. Epinephrine levels were not significantly different between the adrenal veins, possibly due to simultaneous AVS, so we were also able to calculate epinephrine corrected cortisol ratios. Simultaneous B/L AVS with epinephrine to localize autonomous hypercortisolism in the setting of concomitant hyperaldosteronism can be beneficial in guiding surgical management of patients.

Bilateral adrenal hyperplasia is a rare cause of Cushing’s syndrome. Micronodular adrenal hyperplasia, including the primary pigmented micronodular adrenal dysplasia (PPNAD) and the isolated micronodular adrenal hyperplasia (iMAD), can be distinguished from the primary bilateral macronodular adrenal hyperplasia (PBMAH) according to the size of the nodules. They both lead to overt or subclinical CS. In the latter case, PPNAD is usually diagnosed after a systematic screening in patients presenting with Carney complex, while for PBMAH, the diagnosis is often incidental on imaging. Identification of causal genes and genetic counseling also help in the diagnoses. This review discusses the last decades’ findings on genetic and molecular causes of bilateral adrenal hyperplasia, including the several mechanisms altering the PKA pathway, the recent discovery of ARMC5, and the role of the adrenal paracrine regulation. Finally, the treatment of bilateral adrenal hyperplasia will be discussed, focusing on current data on unilateral adrenalectomy.