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Macronodular hyperplasia (MAH) of the adrenal gland is a rare disease usually presenting with Cushing Syndrome. Although usually readily apparent on imaging, an adrenal tumor in an asymptomatic patient may be mistaken for a renal tumor. We present a patient with combined macro- and micro-nodular adrenal hyperplasia masquerading as an upper pole renal mass. The patient underwent a robotic partial nephrectomy and partial adrenalectomy without complication.

Recognizing that adrenal pathology is a component of many genetic syndromes is important for clinical management and genetic counselling. These syndromes may be divided into those which cause excessive adrenal growth including tumours, and those which cause hypoplasia or destruction of the adrenal glands. Syndromes associated with hyperplasia and tumour development include Beckwith-Wiedemann, Li-Fraumeni, Carney complex, McCune-Albright, multiple endocrine neoplasia type 1, hereditary nonpolyposis colorectal carcinoma, familial adenomatous polyposis, primary bilateral macronodular adrenal hyperplasia, and congenital adrenal hyperplasia. Syndromes associated with adrenal dysgenesis or atrophy include X-linked adrenal hypoplasia, IMAGe syndrome, MIRAGE syndrome, familial glucocorticoid deficiency, X-linked adrenoleucodystrophy, Allgrove syndrome, Wolman syndrome, autoimmune polyendocrine syndrome and steroid resistant nephrotic syndrome. The clinical, genetic, and histopathological features of each disease will be discussed.

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 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.

Hypercortisolism is a multisystem disorder that results from inappropriate and excessive glucocorticoid secretion and loss of normal feedback mechanisms of the hypothalamic-pituitary axis. It is broadly divided into adrenocorticotropic hormone (ACTH) dependent and ACTH-independent categories. Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of ACTH-independent hypercortisolism, accounting for less than 2% of cases. It usually presents as hypertension, metabolic abnormalities, thromboembolic, cardiovascular, or endocrine disorders but rarely as a neuropsychiatric illness. Therefore, a delay in the diagnosis and management of cognitive illnesses substantially increases morbidity in these patients. Herein, we report a case of severe psychosis due to Cushing's syndrome with PBMAH. A 49-year-old male with a past medical history of diabetes and hypertension presented with acute onset of confusion. The patient’s uncontrolled hypertension, hypokalemia, metabolic alkalosis, and resistant psychosis to various psychotropic medications raised the suspicion of an underlying metabolic disorder. Further workup revealed an inappropriate suppression of morning (AM) cortisol after administration of dexamethasone and elevated values of serum AM cortisol and 24-hour urinary cortisol, in addition to low ACTH. Computed tomography (CT) of the abdomen and pelvis with intravenous (IV) contrast was performed to evaluate the adrenal gland which showed multiple nonspecific adrenal nodules bilaterally measuring between 3.5 cm - 4.5 cm. The patient was hence diagnosed with hypercortisolism secondary to PBMAH. The patient was treated with ketoconazole after he refused surgery as a treatment option and was noted to have significant improvement in his psychosis within a week, along with improvement of his hypertension, electrolyte abnormalities, and a significant decrease in the 24-hour urine cortisol level. Neuropsychiatric illness is a rare manifestation and an unusual initial presenting symptom of Cushing’s syndrome secondary to primary bilateral macronodular adrenal hyperplasia. A delay in diagnosis often subjects these patients to unnecessary psychotropic medications and prolonged psychiatric hospitalizations. Hence, clinicians must be cognizant of this rare entity when making a diagnostic evaluation to prevent subsequent morbidity and mortality.

Introduction: Adrenal myelolipomas are usually isolated benign adrenal lesions, but can be found adjacent to steroid-secreting adrenocortical tumors. We studied the aberrant regulation of cortisol secretion in a 61 year-old woman with combined bilateral myelolipomas and primary bilateral macronodular adrenal hyperplasia (BMAH) causing Cushing’s syndrome. The goal was to identify potential aberrant ligands and hormone receptors regulating cortisol excess, using both an in vivo investigation protocol and in vitro studies on resected adrenals. Materials and methods: Cortisol response was measured during in vivo tests that transiently modulated the levels of ligands for potential aberrant receptors, including GIP. Response to medical therapies decreasing GIP was monitored. Expression of ACTH and of GIP receptors were examined in resected adrenal tissues by immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR). Results: In vivo, cortisol increased in response to mixed meals (+353%), oral 75 g glucose (+71%), GIP infusion (+416%) and hLH IV (+243%). Suppression of GIP by pasireotide improved cortisol secretion but produced hyperglycemia. The left adrenal was predominantly composed of myelolipoma and strands of BMAH, while the right was mainly composed of BMAH with some foci of myelolipoma on pathology. No ACTH was detectable by immunohistochemistry in BMAH or myelolipomas tissue. Ectopic GIP receptor was confirmed by RT-PCR and immunohistochemistry in BMAH tissues but not in the myelolipomas. Conclusion: This is the first report of interspersed myelolipoma and BMAH with GIP-dependent Cushing’s syndrome. Their simultaneous occurrence may suggest yet to be identified adrenocortical tissue paracrine factors regulated by aberrant receptors which could stimulate adipocyte and hematopoietic cell proliferation.

Introduction: Asymptomatic adrenal masses are often discovered incidentally while testing for unrelated conditions. A very uncommon finding is thickening and increased nodularity of both adrenal glands, which can lead to the patient being diagnosed with subclinical Cushing's syndrome, Conn's syndrome, or both. Case presentation: A 45-year-old African-American man presented to the hospital with a one-month history of increased abdominal girth, bilateral lower extremity edema and shortness of breath, with progressive epigastric abdominal pain which prompted admission. His medical history was relevant for obesity, coronary artery disease and heart failure with reduced ejection fraction. On examination he had a blood pressure of 152/99 mmHg, was diaphoretic, and complained of constant epigastric pain. Multiple purple and pale striae were visible along his abdomen, and he had pitting edema in both lower extremities. His initial laboratory studies showed a potassium of 2.6 mEq/L. A CT scan of the abdomen was relevant for bilaterally enlarged and tortuous adrenal glands, which the patient had no previous knowledge of. Diuresis greatly improved his edema and shortness of breath. Additional laboratory tests showed persistent hypokalemia, normal plasma renin activity and aldosterone, elevated fasting cortisol, normal metanephrines in 24-hour urine collection, and low ACTH level. A suppression test done by administering dexamethasone 0.5 mg every 6 hours for 2 days, was able to suppress the elevated cortisol levels. He was started on spironolactone, and underwent MRI of the abdomen, which confirmed bilateral multinodular adrenal hyperplasia with no imaging characteristics of pheochromocytoma. The patient was discharged home once his clinical status improved. Laboratory studies done at follow-up appointments showed persistently elevated cortisol, normal aldosterone to renin ratio, normal levels of plasma metanephrines and suppressed levels of ACTH. He was also referred to surgery for eventual bilateral adrenalectomy. Discussion: Primary bilateral macronodular adrenal hyperplasia (BMAH) is a very rare cause of endogenous Cushing's syndrome, representing less than 2% of cases. It is characterized by enlarged adrenal glands containing pigmented nodules that secrete excess cortisol and/or aldosterone (1). BMAH is often an incidental finding in patients with subclinical hyper-cortisolism. A low level of plasma ACTH along with bilaterally enlarged adrenal glands on imaging suggest the diagnosis, and this is confirmed with a dexamethasone suppression test. Accurate detection is important for guiding management, which includes pharmacological therapy and bilateral adrenalectomy. Reference: 1. De Venanzi A, Alencar GA, Bourdeau I, Fragoso MCBV, Lacroix A. Primary bilateral macronodular adrenal hyperplasia. Curr Opin Endocrinol Diabetes Obes. 2014 Jun;21(3):177-84.

Background: The incidence of bilateral macronodular adrenal hyperplasia (BMAH) is unknown, but growing in an era of increased utilization of imaging. Coexistence of BMAH and pheochromocytoma has not previously been reported. Clinical Case: A 63-year man presented with enlarging left chest-wall mass found to have a poorly differentiated sarcoma. Staging PET/CT identified a hypermetabolic 2.0 cm left adrenal nodule with SVU of 16.6 concerning for metastasis. Hormonal evaluation included dexamethasone suppression test with 7AM serum cortisol of 24.7 ug/dL (1cm with bilateral gland enlargement consistent with BMAH. Resection of his left adrenal gland was not pursued due to cormorbidities as well as biochemically-silent nature of his pheochromocytoma. To manage his hypercortisolism, he was recently initiated on osilodrostat after completing radiation therapy for his chest-wall sarcoma. Conclusion: This is the first case demonstrating clinical, biochemical, and imaging results consistent with bilateral macronodular adrenal hyperplasia and hypercortisolism also found to have a clinically and biochemically silent, biopsy proven pheochromocytoma. This is also a unique use of osilodrostat to manage BMAH.

Bilateral adrenalectomy or unilateral adrenalectomy and contralateral partial adrenalectomy are indicated for the treatment of ACTH-independent macronodular adrenal hyperplasia. Independent of the surgical procedure, the prognosis is poor. This article discusses a new treatment method and its efficacy for treating nodular adrenal hyperplasia.We performed a retrospective review of the medical records of 12 patients operated on between January 2008 and October 2014 at the First Affiliated Hospital of Zhengzhou University. All patients were treated by laparoscopic subcutaneous transposition of a pedicled adrenal. We performed postoperative monitoring of patients, including clinical symptoms and 24-hour levels of serum-free and urinary-free cortisol.All 12 patients were pathologically confirmed to have nodular adrenal hyperplasia and were followed for an average of 45.5 months (range 24-60 months). The clinical symptoms of all patients disappeared, and the 24-hour plasma-free cortisol and urinary-free cortisol levels were within the normal range.Laparoscopic subcutaneous transposition of a pedicled adrenal is a new and effective method for treating bilateral macronodular adrenal hyperplasia and can achieve long-term remission of Cushing's syndrome.

ARMC5 mutations have recently been identified as a common genetic cause of primary bilateral macronodular adrenal hyperplasia (PBMAH). We aimed to assess the prevalence of ARMC5 germline mutations and correlate genotype with phenotype in a large cohort of PBMAH patients. A multicenter study was performed, collecting patients from different endocrinology units in Italy. Seventy-one PBMAH patients were screened for small mutations and large rearrangements in the ARMC5 gene: 53 were cortisol-secreting (two with a family history of adrenal hyperplasia) and 18 were non-secreting cases of PBMAH. Non-mutated and mutated patients’ clinical phenotypes were compared and related to the type of mutation. A likely causative germline ARMC5 mutation was only identified in cortisol-secreting PBMAH patients (one with a family history of adrenal hyperplasia and ten apparently sporadic cases). Screening in eight first-degree relatives of three index cases revealed four carriers of an ARMC5 mutation. Evidence of a second hit at somatic level was identified in five nodules. Mutated patients had higher cortisol levels (p = 0.062), and more severe hypertension and diabetes (p

ResumenLa hormona luteinizante (LH) y la gonadotropina coriónica humana (hCG) puede inducir esteroidogénesis, hiperplasia y tumorigénesis adrenal a través del estímulo sobre el receptor constitutivo de la LH (R-LHCG) en la corteza adrenal. Los mecanismos fisiopatológicos del síndrome de Cushing adrenal dependiente de LH (SCa-LH) no se han establecido plenamente, pero es reconocida la relación ontogénica adrenal-gonadal con mutua participación de diversos genes, factores de transcripción y enzimas esteroidogénicas como posible causa. El SCa-LH fue descrito en mujeres durante la gestación por el estímulo de hCG y en la posmenopausia ante el aumento de LH, así como en hurones luego de la gonadectomía quirúrgica.AbstractLuteinising hormone (LH) and human chorionic gonadotropin (hCG) can induce steroidogenesis, hyperplasia, and adrenal tumorigenesis through the stimulus of the constitutive LH receptor (R-LHCG) within the adrenal cortex. The pathophysiological mechanisms of luteinising hormone-dependent Cushing's syndrome are not completely understood, but the ontogenic relationship between the adrenal cortex and the gonads, with mutual participation of different genes, transcription factors and steroidogenic enzymes cited as a possible cause, is well-recognised. SCa-LH has been described in pregnant women, as a result of hCG stimulus, and in post-menopausal women, due to increased levels of LH, as well as in ferrets after gonadectomy.

BackgroundBilateral macronodular adrenal hyperplasia (BMAH) is a rare cause of Cushing's syndrome (CS) and its familial clustering has been described previously. Recent studies identified thatARMC5mutations occur frequently in BMAH, but the relation betweenARMC5mutation and the expression of aberrant G-protein-coupled receptor has not been examined in detail yet.MethodsWe 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 examinedin vivoin nine individuals. Sequencing of the coding regions ofARMC5gene was carried out.ResultsMorning ambulating cortisol post 1 mg DST were >50 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. β-blockers led to the reduction of cortisol secretion in all patients with the exception of two who had adrenalectomies because of β-blockers intolerance. We identified a heterozygous germline variant in theARMC5gene 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.ConclusionsSystematic 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 causativeARMC5mutation and the reproducible pattern of aberrant β-adrenergic and V1-vasopressin receptors identified in this family remains to be elucidated.

Adrenocorticotropic hormone-independent macronodular adrenal hyperplasia (AIMAH) is a rare bilateral adrenocorticotropic hormone (ACTH)-independent nodular adrenal hyperplastic disease. Most patients with AIMAH are usually asymptomatic and only a small percentage present with subclinical or apparent Cushing’s syndrome caused by excessive corticosteroid secretion. Herein, we reported the case of a 51-year-old female with bilateral macronodular adrenal hyperplasia with mild fluorodeoxyglucose uptake based on PET/CT imaging findings. Her symptoms resolved after surgical resection of the right adrenal gland.

This is a case report of 59 years old male with adrenocorticotropic hormone ACTH-independent macronodular adrenal hyperplasia (AIMAH), which is a rare cause of Cushing's syndrome. He was detected to have adrenal lesions incidentally on imaging. The biochemical evaluation was suggestive of endogenous ACTH-independent Cushing's syndrome. Contrast Enhanced CT of the abdomen done to characterize the lesion was suggestive of bilateral macro-nodular adrenal hyperplasia. There was no evidence of cushingoid features except for type 2 diabetes mellitus suggestive of subclinical Cushing's. He was not planned for any immediate medical/surgical management since metabolic control was achieved with oral anti-diabetics (OADs) and anti-hypertensive medications. He is on regular follow up with well-controlled sugars and blood pressure.

Context Primary bilateral macronodular adrenal hyperplasia (BMAH) is a rare form of adrenal Cushing syndrome conventionally treated with adrenalectomy. Medical treatment is often reserved for patients not eligible for surgery. However, to date there have been few studies about the efficacy of mifepristone for the treatment of BMAH associated with hypercortisolism. Objective To describe a series of patients with hypercortisolism due to BMAH treated with mifepristone from multiple medical practices. Design We retrospectively assessed four patients treated with mifepristone for hypercortisolism due to BMAH who had either failed unilateral adrenalectomy, declined surgery, or were poor surgical candidates. Results Mifepristone induced clinical improvement and remission of the signs and symptoms of hypercortisolism in all described patients with BMAH. The median treatment duration at the time of efficacy response assessment was 5 months (range: 3 to 18 months). Improvement in cardiometabolic parameters was observed as early as 2 weeks after treatment was started. All patients achieved improvements in glycemic control and hypertension and had significant weight loss. The most common adverse event observed with mifepristone therapy was fatigue. Increases in TSH level occurred in two patients. Conclusion Mifepristone can be an effective medical alternative to surgery in patients with hypercortisolism due to BMAH., Mifepristone treatment may be an effective alternative to bilateral adrenalectomy in patients with hypercortisolism due to primary BMAH.

Background ARMC5 has been identified as the gene responsible for PBMAH (primary bilateral macronodular adrenal hyperplasia). ARMC5 inactivating mutations are reported in 20 to 25% of PBMAH patients. ARMC5 is considered as a tumor suppressor gene controlling apoptosis and regulating steroidogenesis. The mechanisms of action of ARMC5 are unknown. The structure of the ARMC5 protein contains ARM repeats and a BTB domain, patterns known to play a role in protein-protein interactions. Therefore identification of proteins that interact with ARMC5 and study of the mechanisms of this interaction will help to understand its function. By co-immunoprecipitation followed by mass spectrometry in HEK293 cells we identified a potential interaction between ARMC5 and Cullin3 (Cul3), also suggested in online databases and by 2 Hybrid Assay (Hu et al., 2017). Cul3 is a protein that mediates the ubiquitination process and subsequent degradation of specific protein substrates. Therefore, the aim of this study was to confirm this interaction and to investigate its mechanisms. Methods We used immunoprecipitation experiments with HA-tagged Cul3 and the bioluminescence resonance energy transfer (BRET) proximity assay in HEK293 cells in order to confirm and investigate the interaction of ARMC5 with Cul3. Results ARMC5 co-immunoprecipitated with HA-Cul3 and a hyperbolic BRET saturation curve was observed with YFP-Cul3 and ARMC5-Luc indicating a specific close proximity between these two proteins. We have also observed that a missense mutation in the BTB domain (p.L754P) of ARMC5 disrupts the interaction with Cul3. Altogether, these complementary approaches demonstrate that ARMC5 and Cul3 form a complex involving the BTB domain of ARMC5. Conclusion These data demonstrate that Cul3 is an ARMC5 partner. A likely direct interaction involves the BTB domain of ARMC5 and can be altered by pathogenic ARMC5 missense mutations. This suggests that ARMC5 participates in the ubiquitination process and open new perspectives in the pathophysiology of PBMAH.

Background Bilateral macronodular adrenal hyperplasia (BMAH) is a rare cause of Cushing’s syndrome (CS). BMAH is predominantly believed to be caused by two mutations, a germline and somatic one, respectively, as described in the two-hit hypothesis. In many familial cases of BMAH, mutations in armadillo repeat containing 5 (ARMC5), a putative tumor suppressor gene, are thought to induce the disorder. The objective of this study was to report a case in which the patient presented with BMAH induced by a novel heterozygous germline ARMC5 mutation (c. 517C > T, p. Arg173*) alone rather than a two-hit mutation. Case presentation A 51-year-old woman was identified with masses in the bilateral adrenals. Serum cortisol levels were increased significantly both in the morning (08:00 AM) and late at night (24:00 AM), while plasma adrenocorticotropic hormone was normal. The patient underwent a left adrenalectomy and histopathology substantiated the BMAH diagnosis. WES of the germline DNA discovered a novel heterozygous germline ARMC5 mutation (c. 517C > T, p. Arg173*) and in silico analysis predicted that the mutation significantly impaired protein function, resulting in inactivated ARMC5. Subsequently, WES of the tumor specimen identified 79 somatic single nucleotide polymorphisms (SNPs)/insertion-deletion (indel) mutations, including 32 missense/nonsense/splice/stop-loss mutations. None of these mutations were CS-related. Conclusions A novel germline ARMC5 mutation (c. 517C > T, p. Arg173*) was identified that induced BMAH alone without a second mutation. ARMC5 sequencing may improve the identification of clinical forms of BMAH and allow earlier diagnosis of this disease. Electronic supplementary material The online version of this article (10.1186/s12881-018-0564-2) contains supplementary material, which is available to authorized users.

To investigate Armadillo repeat-containing 5 (ARMC5) mutations in Chinese patients with familial and sporadic primary bilateral macronodular adrenal hyperplasia (PBMAH), we performed clinical data collection and ARMC5 sequencing for three PBMAH families and 23 sporadic PBMAH patients. ARMC5 pathogenic germline mutations were identified in all 3 PBMAH families. Secondary ARMC5 somatic mutations were found in two adrenal nodules from two PBMAH family members with ARMC5 germline mutations. PBMAH family members with ARMC5 pathogenic germline mutations displayed various clinical manifestations. ARMC5 pathogenic germline mutations were identified in 5 sporadic PBMAH patients among whom one patient displayed both hypercortisolism and primary aldosteronism. We detected a total of 10 ARMC5 pathogenic mutations, of which 8 had not been previously reported. Our results suggest that ARMC5 pathogenic germline mutations are common in familial and sporadic Chinese PBMAH patients, and demonstrate the importance of ARMC5 screening in PBMAH family members to detect patients with insidious PBMAH.

Idiopathic hyperaldosteronism (IHA) due to bilateral adrenal hyperplasia is the most common subtype of primary aldosteronism (PA). The pathogenesis of IHA is still unknown, but the bilateral disease suggests a potential predisposing genetic alteration. Heterozygous germline mutations of armadillo repeat containing 5 (ARMC5) have been shown to be associated with hypercortisolism due to sporadic primary bilateral macronodular adrenal hyperplasia and are also observed in African-American PA patients. We investigated the presence of germline ARMC5 mutations in a group of PA patients who had bilateral computed tomography-detectable adrenal alterations. We sequenced the entire coding region of ARMC5 and all intron/exon boundaries in 39 patients (37 Caucasians and 2 black Africans) with confirmed PA (8 unilateral, 27 bilateral and 4 undetermined subtype) and bilateral adrenal lesions. We identified 11 common variants, 5 rare variants with a minor allele frequency

Long-term consequences of cortisol excess are frequent despite appropriate treatment after cure of Cushing's syndrome. This might be due to diagnostic delay, often difficult to reduce in rare diseases. The identification of a genetic predisposing factor might help to improve early diagnosis by familial screening. Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing's syndrome. Hypercortisolism in PBMAH is most often diagnosed between the fifth and sixth decades of life. The bilateral nature of the adrenocortical tumors and the occurrence of rare clear familial forms suggest a genetic origin. Indeed, a limited subset of PBMAH can be observed as part of multiple tumors syndromes due to alterations of the APC, Menin or Fumarate Hydratase genes. Rare variants of the phosphodiesterases PDE11A have been associated with PBMAH. The recent identification of ARMC5 germline alterations in 25–50% of PBMAH patients without obvious familial history or associated tumors opens new perspectives. ARMC5 alterations follow the model of a tumor suppressor gene: a first germline inactivating mutation of this 16p located gene is followed by a somatic secondary hit on the other allele (inactivating mutation or allelic loss). Functional studies demonstrate that ARMC5 controls apoptosis and steroid synthesis. The phenotype of index cases patients with the mutation seems more severe than the one of WT index cases. However, phenotype variability within a family is often observed. This review summarizes the genetics of PBMAH, focusing on ARMC5, which offer new perspectives for early diagnosis of Cushing's syndrome.

Objective: To review the genetic basis of bilateral macronodular hyperplasia (BMAH). Methods: Case presentation, review of literature, table, and bullet point conclusions. Results: BMAH, also known as adrenocorticotropic hormone (ACTH)-independent macronodular hyperplasia (AIMH), can cause Cushing syndrome or mild hypercortisolism. Recent studies have demonstrated that hyperplastic tissue reproduces ectopic ACTH, implying that BMAH is the more proper term, as the syndrome is not ACTH-independent. BMAH was thought to be sporadic, but recent data have shown that there is likely a genetic component in the majority of cases. Mutations in ARMC5, a putative suppressor gene, have been found in many familial cases of BMAH and are thought to be responsible for the disorder. As these nodules inefficiently produce cortisol, large nodules are required to produce a clinical syndrome. ARMC5 likely requires a second somatic mutation to become clinically apparent. Clinical manifestations are not generally noted until the fifth to sixth decades of life. Conclusion: BMAH is an underrecognized genetic condition that can lead to Cushing syndrome and should be screened for in patients and susceptible family members. Abbreviations: ACTH = adrenocorticotropic hormone AIMAH = ACTH-independent macronodular adrenal hyperplasia ARMC5 = armadillo-repeat containing 5 BMAH = bilateral macronodular adrenal hyperplasia CAH = congenital adrenal hyperplasia CT = computed tomography MEN1 = multiple endocrine neoplasia 1 UFC = urinary free cortisol

ACTH-independent macronodular adrenal hyperplasia is a rare cause of Cushing's syndrome (CS), accounting for

Objective: Cushing syndrome is an endocrine disorder resulting from prolonged exposure to excess cortisol that can lead to significant morbidity and mortality. Surgery is the first-line treatment for Cushing syndrome. Mifepristone is a glucocorticoid receptor (GR) antagonist that is used in the medical treatment of Cushing syndrome. Methods: We describe the clinical and hormonal responses of 2 patients with adrenal (adrenocorticotropic hormone lACTH]-independent) Cushing syndrome who were treated with mifepristone. The first case was a 41-year-old male with Cushing syndrome secondary to primary pigmented nodular adrenocortical disease associated with Carney complex. He was treated with mifepristone prior to definitive surgical management. During medical treatment with mifepristone, he lost 44 pounds, and his Cushingoid features resolved. The second case was a 65-year-old male with Cushing syndrome secondary to ACTH-independent macronodular adrenal hyperplasia (AIMAD). Cushing syndrome persisted after unilateral adrenalectomy, but medical comorbidities precluded a second surgery. Ketoconazole failed to adequately control his symptoms, and he was treated with mifepristone. During medical treatment with mifepristone, he lost 12 pounds, and his Cushingoid features and cortisol excessrelated comorbidities improved. In both cases, ACTH was suppressed prior to treatment and rose into the normal range within 3 months of initiating pharmacologic therapy. Conclusions: Mifepristone is a GR antagonist that can be used in the medical management of cortisol excess due to ACTH-independent Cushing syndrome. Hormonal responses indicating recovery of the hypothalamus-pituitary adrenal (HPA) axis can be seen within 3 months of therapy. Abbreviations: ACTH adrenocorticotropin hormone CT computed tomography DHEAS dehydroepiandrosterone sulfate GR glucocorticoid receptors HPA hypothalamic-pituitary adrenal axis MR mineralocorticoid receptors UFC urinary free cortisol

Primary macronodular adrenal hyperplasia (PMAH), also known in the past as bilateral macronodular adrenalhyperplasia or adrenocorticotropin (ACTH)-independent macronodular adrenal hyperplasia, is a rare type of Cushing's syndrome (CS) and is associated with bilateralenlargement of the adrenal glands. It accounts for

Bilateral macronodular adrenal hyperplasia (BMAH) is a relatively rare cause of Cushing's Syndrome (CS). In recent years, growing evidence has shown that steroidogenesis is regulated by aberrant G-protein-coupled receptors (GPCRs) expression and their ligands, in a significant proportion of patients with BMAH. The screening of patients with overt or subclinical CS demonstrates the frequent expression of several GPCRs that opened the option to potential therapeutic applications. Thus, several studies have demonstrated that targeting the involved receptor with specific antagonists may result in a more or less effective control of cortisol excess. Bilateral adrenalectomy has traditionally been considered the treatment of choice for BMAH. However, unilateral adrenalectomy has been recently proposed as an alternative in selective patients to avoid the long-term necessity of gluco/mineralocorticoid replacement. Adrenal steroidogenesis inhibitors remain a valid option when medical treatment is needed due to high surgical risk.

Context: Elevated human choriogonadotropin (hCG) may stimulate aberrantly expressed luteinizing hormone (LH)/hCG receptor (LHCGR) in adrenal glands, resulting in pregnancy-induced bilateral macronodular adrenal hyperplasia and transient Cushing syndrome (CS). Objective: To determine the role of LHCGR in transient, pregnancy-induced CS. Design, Setting, Patient, and Intervention: We investigated the functional implications of LHCGRs in a patient presenting, at a tertiary referral center, with repeated pregnancy-induced CS with bilateral adrenal hyperplasia, resolving after parturition. Main Outcome Measures and Results: Acute testing for aberrant hormone receptors was negative except for arginine vasopressin (AVP)–increased cortisol secretion. Long-term hCG stimulation induced hypercortisolism, which was unsuppressed by dexamethasone. Postadrenalectomy histopathology demonstrated steroidogenically active adrenocortical hyperplasia and ectopic cortical cell clusters in the medulla. Quantitative polymerase chain reaction showed upregulated expression of LHCGR, transcription factors GATA4, ZFPM2, and proopiomelanocortin (POMC), AVP receptors (AVPRs) AVPR1A and AVPR2, and downregulated melanocortin 2 receptor (MC2R) vs control adrenals. LHCGR was localized in subcapsular, zona glomerulosa, and hyperplastic cells. Single adrenocorticotropic hormone–positive medullary cells were demonstrated in the zona reticularis. The role of adrenal adrenocorticotropic hormone was considered negligible due to downregulated MC2R. Coexpression of CYP11B1/CYP11B2 and AVPR1A/AVPR2 was observed in ectopic cortical cells in the medulla. hCG stimulation of the patient’s adrenal cell cultures significantly increased cyclic adenosine monophosphate, corticosterone, 11-deoxycortisol, cortisol, and androstenedione production. CTNNB1, PRKAR1A, ARMC5, and PRKACA gene mutational analyses were negative. Conclusion: Nongenetic, transient, somatic mutation-independent, pregnancy-induced CS was due to hCG-stimulated transformation of LHCGR-positive undifferentiated subcapsular cells (presumably adrenocortical progenitors) into LHCGR-positive hyperplastic cortical cells. These cells respond to hCG stimulation with cortisol secretion. Without the ligand, they persist with aberrant LHCGR expression and the ability to respond to the same stimulus., Précis: Pregnancy-induced CS due to hCG-stimulated transformation of LHCGR-positive undifferentiated subcapsular cells into LHCGR-positive hyperplastic cortical cells with hCG-stimulated cortisol secretion.

Germline loss-of-function mutations in the armadillo-repeat-containing 5 (ARMC5) gene are an established cause of Cushing's syndrome due to bilateral macronodular adrenal hyperplasia (BMAH), 1,2 and may play a role in primary aldosteronism. 3 As familial hyperaldosteronism type II (FH-II) has a presumed genetic basis, 4 we hypothesised that germline ARMC5 mutations underlie FH-II. We interrogated whole-exome sequencing data from four FH-II families. We did not identify any pathogenic ARMC5 variants which segregated with the phenotype of primary aldosteronism. Refereed/Peer-reviewed

Context: Maffucci syndrome is a rare, nonhereditary, mesodermal dysplastic disease characterized by the presence of multiple hemangiomas and enchondromas. This pathological condition, which is often unrecognized, is associated with a high prevalence of benign and malignant endocrine tumors involving pituitary, adrenal, thyroid, and parathyroid glands. Case Description: We describe the case of a young patient presenting a history suggestive of secondary arterial hypertension and typical features of Maffucci syndrome (multiple hemangiomas and enchondromas), which were unrecognized over the previous 3 decades. Given that endocrine diseases are common causes of secondary arterial hypertension and are often associated with Maffucci syndrome, a comprehensive diagnostic workup was performed, revealing the presence of large bilateral adrenal masses (70 mm right, 35 mm left) and autonomous cortisol secretion (adrenocorticotropic hormone–independent Cushing syndrome). The patient underwent a bilateral adrenalectomy, and steroid replacement therapy was initiated. Surgery resulted in a normalization of arterial blood pressure, and antihypertensive treatment was discontinued. Histological examinations revealed morphological features of primary bilateral macronodular adrenal hyperplasia. Conclusions: Early recognition and lifelong monitoring of Maffucci syndrome is required to identify and treat possible associated endocrine diseases and malignancies. Among them, unilateral cortical adrenal masses have been previously described, but to our knowledge, this is the first reported case of Maffucci syndrome associated with primary bilateral macronodular adrenal hyperplasia. Additional studies are needed to establish the etiopathological link between these 2 entities and, more in general, between Maffucci syndrome and endocrine diseases, but possible common genetic alterations may be suggested., Précis: Establishing the diagnosis of Maffucci syndrome in a patient with suspected secondary arterial hypertension prompted an extensive workup revealing primary bilateral macronodular adrenal hyperplasia.

Primary macronodular adrenal hyperplasia (PMAH) is a rare cause of Cushing's syndrome, usually characterized by functioning adrenal macronodules and increased cortisol production. Familial clustering of PMAH has been described, suggesting an inherited genetic cause for this condition.The aim of the present study was to identify the gene responsible for familial PMAH.Forty-seven individuals of a Brazilian family with PMAH were evaluated. A single-nucleotide polymorphism-based genome-wide linkage analysis followed by whole-exome sequencing were then performed in selected family members. Additionally, 29 other patients with PMAH and 125 randomly selected healthy individuals were studied to validate the genetic findings. Moreover, PMAH tissue was also analyzed through whole-exome sequencing, conventional sequencing, and microsatellite analysis.A heterozygous germline variant in the ARMC5 gene (p.Leu365Pro) was identified by whole-exome sequencing in a candidate genomic region (16p11.2). Subsequently, the same variant was confirmed by conventional sequencing in all 16 affected family members. The variant was predicted to be damaging by in silico methods and was not found in available online databases or in the 125 selected healthy individuals. Seven additional ARMC5 variants were subsequently identified in 5 of 21 patients with apparently sporadic PMAH and in 2 of 3 families with the disease. Further molecular analysis identified a somatic mutational event in 4 patients whose adrenal tissue was available.Inherited autosomal dominant mutations in the ARMC5 gene are a frequent cause of PMAH. Biallelic inactivation of ARMC5 is consistent with its role as a potential tumor suppressor gene.

Inactivating germline mutations of the probable tumor suppressor gene, armadillo repeat containing 5 (ARMC5), have recently been identified as a genetic cause of macronodular adrenal hyperplasia (MAH).We searched for ARMC5 mutations in a large cohort of patients with MAH. The clinical phenotype of patients with and without ARMC5 mutations was compared.Blood DNA from 34 MAH patients was genotyped using Sanger sequencing. Diurnal serum cortisol measurements, plasma ACTH levels, urinary steroids, 6-day Liddle's test, adrenal computed tomography, and weight of adrenal glands at adrenalectomy were assessed.Germline ARMC5 mutations were found in 15 of 34 patients (44.1%). In silico analysis of the mutations indicated that seven (20.6%) predicted major implications for gene function. Late-night cortisol levels were higher in patients with ARMC5-damaging mutations compared with those without and/or with nonpathogenic mutations (14.5 ± 5.6 vs 6.7 ± 4.3, P.001). All patients carrying a pathogenic ARMC5 mutation had clinical Cushing's syndrome (seven of seven, 100%) compared with 14 of 27 (52%) of those without or with mutations that were predicted to be benign (P = .029). Repeated-measures analysis showed overall higher urinary 17-hydroxycorticosteroids and free cortisol values in the patients with ARMC5-damaging mutations during the 6-day Liddle's test (P = .0002).ARMC5 mutations are implicated in clinically severe Cushing's syndrome associated with MAH. Knowledge of a patient's ARMC5 status has important clinical implications for the diagnosis of Cushing's syndrome and genetic counseling of patients and their families.

Objective To investigate the efficacy of medical treatment as an alternative option to bilateral adrenalectomy in patients with cortisol excess due to adrenocorticotropic hormone (ACTH) independent macronodular adrenal hyperplasia (AIMAH). Methods We focused on the efficacy of somatostatin analogues in a patient with food-dependent AIMAH and of leuprolide acetate in a patient with AIMAH due to aberrant LH/hCG receptor expression. Results Two female patients with bilateral macronodular adrenal hyperplasia and cortisol excess were evaluated for the presence of aberrant cortisol responses. One patient demonstrated an aberrant response to mixed meal and the other, a menopausal female, to luteinizing hormonereleasing hormone (LHRH) and human chorionic gonadotropin (hCG) administration. In the first patient, subcutaneous octreotide was administered prior to mixed meal and completely abolished food-induced cortisol secretion. Thus, the patient was treated with the long-acting somatostatin analogue octreotide long-acting release (LAR) for 3 months. There was no control of cortisol excess upon reevaluation and acute subcutaneous octreotide administration prior to meal was no longer effective in blocking food-induced cortisol secretion. The second patient successfully responded to leuprolide acetate and, for 40 months, her cortisol excess remains in long-term control. Conclusion A luteinizing hormone/human chorionic gonadotropin (LH/hCG) responsive patient with AIMAH sustained long-term control of cortisol excess on leuprolide acetate. In contrast, in a meal-responsive patient with apparent gastric inhibitory polypeptide (GIP) dependent AIMAH, did not achieve remission under somatostatin analogues. (Endocr Pract. 2013;19:e77-e82)

Context: Recurrent somatic mutations in KCNJ5, CACNA1D, ATP1A1, and ATP2B3 have been identified in aldosterone-producing adenomas (APAs). The question as to whether they are responsible for both nodulation and aldosterone production is not solved. Case Description: We describe the case of a young patient who was diagnosed with severe arterial hypertension due to primary aldosteronism at age 26 years, followed by hemorrhagic stroke 4 years later. Abdominal computed tomography showed bilateral macronodular adrenal hyperplasia. Identification of lateralized aldosterone secretion led to right adrenalectomy, followed by normalization of biochemical and hormonal parameters and amelioration of blood pressure. The resected adrenal showed three nodules, one of them expressing aldosterone synthase and harboring a somatic KNCJ5 mutation. A Weiss revisited index of 3 of the APA prompted us to perform a second 18F-2-fluoro-2-deoxy-D-glucose-positron emission tomography after surgery, which revealed abnormal rectal activity despite the absence of clinical symptoms. Gastrointestinal exploration showed multiple polyps with severe dysplasia, and the diagnosis of familial adenomatous polyposis was established in the presence of a germline heterozygous APC gene mutation. Sequencing of somatic DNA from the APA and a second adrenal nodule revealed biallelic APC inactivation due to loss of heterozygosity in both nodules. Conclusions: This case report underlines the need for establishing the frequency of germline APC variants in patients with primary aldosteronism and bilateral macronodular adrenal hyperplasia because their presence may predispose to APA development and severe hypertension well before the first familial adenomatous polyposis symptoms appear. From a mechanistic point of view, it supports a two-hit model for APA development, whereby the first hit drives increased cell proliferation whereas the second hit specifies the pattern of hormonal secretion.

International audience; In the normal human adrenal gland, steroid secretion is regulated by a complex network of autocrine/paracrine interactions involving bioactive signals released by endothelial cells, nerve terminals, chromaffin cells, immunocompetent cells, and adrenocortical cells themselves. ACTH can be locally produced by medullary chromaffin cells and is, therefore, a major mediator of the corticomedullary functional interplay. Plasma ACTH also triggers the release of angiogenic and vasoactive agents from adrenocortical cells and adrenal mast cells and, thus, indirectly regulates steroid production through modulation of the adrenal blood flow. Adrenocortical neoplasms associated with steroid hypersecretion exhibit molecular and cellular defects that tend to reinforce the influence of paracrine regulatory loops on corticosteroidogenesis. Especially, ACTH has been found to be abnormally synthesized in bilateral macronodular adrenal hyperplasia responsible for hypercortisolism. In these tissues, ACTH is detected in a subpopulation of adrenocortical cells that express gonadal markers. This observation suggests that ectopic production of ACTH may result from impaired embryogenesis leading to abnormal maturation of the adrenogonadal primordium. Globally, the current literature indicates that ACTH is a major player in the autocrine/paracrine processes occurring in the adrenal gland in both physiological and pathological conditions.

Мета роботи – проаналізувати сучасні літературні відомості та власні клінічні спостереження щодо патогенезу та діагностично-лікувальних особливостей АІМАН.Матеріали та методи. Матеріалами для літературного аналізу слугували наукові друковані та інтернет-ресурси. Власні спостереження спиралися на аналіз комп’ютерної бази даних спеціалізованої клініки ендокринної хірургії, що налічує більш як 900 пацієнтів з хірургічними захворюваннями НЗ, в тому числі 34 хворих, які були віднесені за комплексом ознак до АІМАН.Результати та обговорення. АІМАН серед пацієнтів, оперованих з різних причин на НЗ, складає істотну частку (3,8%). Середній вік хворих становив (53±7) років (42–71 рік), серед яких жінок – 23, чоловіків – 7 (23,3%). У половини пацієнтів разом із СК виявлявся первинний гіперальдостеронізм. Пацієнти мали ознаки переважно субклінічного СК з домінуючим синдромом у вигляді артеріальної гіпертензії, цукрового діабету, остеопорозу, ожиріння. Усім після верифікації СК, супресованого АКТГ та візуалізації виконано однобічну лапароскопічну адреналектомію. Віддалені результати відстежені для 30 пацієнтів у період до 1 року та у 25 хворих – до 5,5 року. Клінічне покращення зареєстроване у 93% та 76% відповідно. У всіх пацієнтів рівень кортизолу крові нормалізувався, лабораторного рецидиву СК не спостерігалося.Висновки. Двобічні гіперпластичні ураження НЗ із низькою рентгенологічною щільністю утворень мають розглядатись як імовірний варіант АІМАН та підлягати дослідженню на прихований СК. Лапароскопічна адреналектомія з боку більш виражених гіперпластичних змін за даними візуалізаційних обстежень дозволяє досягти тривалої ремісії у більшості пацієнтів та не призводить до надниркової недостатності., Цель работы – проанализировать современные литературные сведения и собственные клинические наблюдения, касающиеся патогенеза, диагностических и лечебных особенностей АIМАН.Материалы и методы. Материалом литературного анализа служили научные печатные и интернет-ресурсы. Собственные наблюдения основаны на анализе компьютерной базы данных специализированной клиники эндокринной хирургии, которая насчитывает более 900 пациентов с хирургическими заболеваниями НЖ, в том числе 34 больных, относящихся по комплексу признаков к АIМАН.Результаты и обсуждение. АIМАН среди пациентов, оперированных на НЖ по разным причинам, составляет существенную часть (3,8%). Средний возраст больных составил (53±7) лет (42–71 год), из которых женщин – 23, мужчин – 7 (23,3%). У половины пациентов СК сопровождался первичным гиперальдостеронизмом. Пациенты имели признаки преимущественно субклинического СК с доминирующим синдромом в виде артериальной гипертензии, сахарного диабета, остеопороза, ожирения. Всем после верификации СК, супрессивного АКТГ и визуализации НЖ выполнена односторонняя лапароскопическая адреналэктомия. Отдаленные результаты отслежены у 30 пациентов в период до 1 года и у 25 больных – до 5,5 года. Клиническое улучшение зарегистрировано в 93% и 76% соответственно. У всех пациентов уровень кортизола крови нормализовался, лабораторного рецидива СК не наблюдалось.Выводы. Двусторонние гиперпластические поражения НЖ с низкой рентгенологической плотностью образований должны рассматриваться как вероятный вариант АIМАН и подлежать исследованию на скрытый СК. Лапароскопическая адреналэктомия со стороны более выраженных гиперпластических изменений по данным визуализационных обследований позволяет достичь длительной ремиссии у большинства пациентов и не вызывает надпочечниковой недостаточности., Aim. To analyze modern medical literature and own clinical data related to pathogenesis, diagnosis and treatment of AIMAH patients.Material and methods. Published and electronic resources were analyzed. Own data were received from institutional computed database, collected data of more than 900 patients after adrenalectomies, performed during the last 15 years, including 34 (3,8%) adequately examined patients with AIMAH.Results and discussion. AIMAH is not a rare condition among endogenous adrenal CS. Average age of patients was (53+_7) years (42–71 years), males comprised 23,3% (7 persons). Primary hyperaldosteronism was simultaneously diagnosed with CS in one half of patients with AIMAH. Clinical presentation of disease comprised with predominantly subclinical CS accompanied by arterial hypertension, diabetes mellitus, osteoporosis and obesity. All patients after confirmation of CS, ACTH-independancy and positive visualization were treated by unilateral laparoscopic adrenalectomy. Follow-up was carried out for 30 patients up to 1 year and for 25 patients – until 5,5 years after surgery. Clinical improvement of symptoms has been established for 93% and 76% correspondingly. All patients demonstrated normalization of serum level of cortisol, not a single case of laboratory relapse of CS was confirmed.Conclusion. Bilateral hyperplastic lesions of adrenals with low radiologic density should be considered as possible AIMAH and should undergo investigation on occult CS. Laparoscopic adrenalectomy on the side of more prominent hyperplasia leads to long term remission in most of patients and does not lead to adrenal insufficiency.

Aim. To analyze modern medical literature and own clinical data related to pathogenesis, diagnosis and treatment of AIMAH patients.Material and methods. Published and electronic resources were analyzed. Own data were received from institutional computed database, collected data of more than 900 patients after adrenalectomies, performed during the last 15 years, including 34 (3,8%) adequately examined patients with AIMAH.Results and discussion. AIMAH is not a rare condition among endogenous adrenal CS. Average age of patients was (53+_7) years (42–71 years), males comprised 23,3% (7 persons). Primary hyperaldosteronism was simultaneously diagnosed with CS in one half of patients with AIMAH. Clinical presentation of disease comprised with predominantly subclinical CS accompanied by arterial hypertension, diabetes mellitus, osteoporosis and obesity. All patients after confirmation of CS, ACTH-independancy and positive visualization were treated by unilateral laparoscopic adrenalectomy. Follow-up was carried out for 30 patients up to 1 year and for 25 patients – until 5,5 years after surgery. Clinical improvement of symptoms has been established for 93% and 76% correspondingly. All patients demonstrated normalization of serum level of cortisol, not a single case of laboratory relapse of CS was confirmed.Conclusion. Bilateral hyperplastic lesions of adrenals with low radiologic density should be considered as possible AIMAH and should undergo investigation on occult CS. Laparoscopic adrenalectomy on the side of more prominent hyperplasia leads to long term remission in most of patients and does not lead to adrenal insufficiency., Цель работы – проанализировать современные литературные сведения и собственные клинические наблюдения, касающиеся патогенеза, диагностических и лечебных особенностей АIМАН.Материалы и методы. Материалом литературного анализа служили научные печатные и интернет-ресурсы. Собственные наблюдения основаны на анализе компьютерной базы данных специализированной клиники эндокринной хирургии, которая насчитывает более 900 пациентов с хирургическими заболеваниями НЖ, в том числе 34 больных, относящихся по комплексу признаков к АIМАН.Результаты и обсуждение. АIМАН среди пациентов, оперированных на НЖ по разным причинам, составляет существенную часть (3,8%). Средний возраст больных составил (53±7) лет (42–71 год), из которых женщин – 23, мужчин – 7 (23,3%). У половины пациентов СК сопровождался первичным гиперальдостеронизмом. Пациенты имели признаки преимущественно субклинического СК с доминирующим синдромом в виде артериальной гипертензии, сахарного диабета, остеопороза, ожирения. Всем после верификации СК, супрессивного АКТГ и визуализации НЖ выполнена односторонняя лапароскопическая адреналэктомия. Отдаленные результаты отслежены у 30 пациентов в период до 1 года и у 25 больных – до 5,5 года. Клиническое улучшение зарегистрировано в 93% и 76% соответственно. У всех пациентов уровень кортизола крови нормализовался, лабораторного рецидива СК не наблюдалось.Выводы. Двусторонние гиперпластические поражения НЖ с низкой рентгенологической плотностью образований должны рассматриваться как вероятный вариант АIМАН и подлежать исследованию на скрытый СК. Лапароскопическая адреналэктомия со стороны более выраженных гиперпластических изменений по данным визуализационных обследований позволяет достичь длительной ремиссии у большинства пациентов и не вызывает надпочечниковой недостаточности., Мета роботи – проаналізувати сучасні літературні відомості та власні клінічні спостереження щодо патогенезу та діагностично-лікувальних особливостей АІМАН.Матеріали та методи. Матеріалами для літературного аналізу слугували наукові друковані та інтернет-ресурси. Власні спостереження спиралися на аналіз комп’ютерної бази даних спеціалізованої клініки ендокринної хірургії, що налічує більш як 900 пацієнтів з хірургічними захворюваннями НЗ, в тому числі 34 хворих, які були віднесені за комплексом ознак до АІМАН.Результати та обговорення. АІМАН серед пацієнтів, оперованих з різних причин на НЗ, складає істотну частку (3,8%). Середній вік хворих становив (53±7) років (42–71 рік), серед яких жінок – 23, чоловіків – 7 (23,3%). У половини пацієнтів разом із СК виявлявся первинний гіперальдостеронізм. Пацієнти мали ознаки переважно субклінічного СК з домінуючим синдромом у вигляді артеріальної гіпертензії, цукрового діабету, остеопорозу, ожиріння. Усім після верифікації СК, супресованого АКТГ та візуалізації виконано однобічну лапароскопічну адреналектомію. Віддалені результати відстежені для 30 пацієнтів у період до 1 року та у 25 хворих – до 5,5 року. Клінічне покращення зареєстроване у 93% та 76% відповідно. У всіх пацієнтів рівень кортизолу крові нормалізувався, лабораторного рецидиву СК не спостерігалося.Висновки. Двобічні гіперпластичні ураження НЗ із низькою рентгенологічною щільністю утворень мають розглядатись як імовірний варіант АІМАН та підлягати дослідженню на прихований СК. Лапароскопічна адреналектомія з боку більш виражених гіперпластичних змін за даними візуалізаційних обстежень дозволяє досягти тривалої ремісії у більшості пацієнтів та не призводить до надниркової недостатності.

The Editorial on the Research Topic Adrenal cortex: from physiology to disease The adrenal gland plays essential roles in the control of body homeostasis, stress, and immune responses. The adrenal cortex represents up to 90% of the gland and is specialized in the production of adrenal steroids. The coordinate production of these steroids relies on adrenal cortex zonation, which corresponds to the establishment of distinct concentric functional zones in the perinatal period: outermost zona glomerulosa synthesizes mineralocorticoids, zona fasciculata produces glucocorticoids, and innermost zona reticularis synthesizes both glucocorticoids and adrenal androgens. This zonal organization has to be maintained throughout the life of the individual, despite constant centripetal tissue renewal. The review by Pihlajoki et al. summarizes the latest findings on the mechanisms of adrenal cortex renewal, which relies on outer cortex progenitors recruitment and lineage conversion along cell migration within the cortex. This paper also provides a comprehensive overview of the hormones, signaling pathways, and transcription factors that control these processes to allow for on-demand adaptation of cortical function and maintenance of adrenal homeostasis. Defects in adrenal development and maintenance are associated with adrenal insufficiency, a life threatening condition for which lifelong hormonal replacement therapies can be challenging. The review by Ruiz-Babot and colleagues sheds light on novel developments in the field of adrenal replacement, including pluripotent cell reprograming and the use of encapsulating devices with semi-permeable membranes to avoid immune rejection of grafts. These promising approaches could pave the way for future clinical management of adrenal-insufficiency patients. While adrenal insufficiency is clinically problematic, the opposite situation in which adrenal steroid production is increased also raises significant clinical concerns. Hypercortisolism results in Cushing’s syndrome associated with central obesity, arterial hypertension, immunosuppression, and depression. Hyperaldosteronism is associated with high blood pressure and profound cardiovascular and renal alterations, which result in increased risk of cardiovascular failure. These highly morbid syndromes are the consequence of either benign hyperplasia and tumors or adrenocortical cancer (ACC). The review by Boulkroun and colleagues establishes the molecular bases of normal control of aldosterone production and elaborates on recent next-generation sequencing (NGS) analyses that allowed identification of mutations in potassium and calcium channels as key players in the development of hyperaldosteronism. Even if these mutations can explain increased aldosterone secretion, they are unlikely to account for tumor growth. Boulkroun et al. summarize data showing that deregulated cell growth in aldosterone-producing adenomas is likely to result from WNT and SHH signaling pathway activation in these tumors. Deregulated protein kinase A (PKA) signaling is a common theme in adrenal tumors associated with ACTH-independent hypercortisolism. These include primary pigmented adrenocortical disease (PPNAD), adrenal adenomas, bilateral macronodular adrenal hyperplasia (BMAH), and adrenal cancer. The review by Berthon et al. provides in-depth insight into the genetic causes of deregulated PKA signaling, including inactivating PRKAR1A mutations in PPNAD and activating PRKACA mutations in cortisol-producing adenomas. Interestingly, mutations in either PRKAR1A or PRKACA were not found in BMAH. The review by Drougat et al. emphasizes the discovery of mutations in ARMC5 as a likely cause of these particular benign adrenal tumors and elaborates on potential pathogenic mechanisms. Lefebvre et al. shed another light on BMAH by focusing on the paracrine regulation of cortisol secretion. They gather data showing that cortisol secretion is stimulated by the release of a number of factors either produced by non-steroidogenic cells within the cortex (mast, chromaffin, and endothelial cells) or by a subset of aberrantly differentiated steroidogenic cells that can release serotonin or even ACTH within the hyperplastic tissue. They further suggest that aberrant ACTH production and expression of ectopic receptors, such as the receptors of LH, GIP, and 5-HT7, may be the result of aberrant differentiation of gonadal-like cells, triggered by driver mutations, such as ARMC5 inactivation. Beyond steroid hormone excess, which is also observed in about 40–60% of patients, ACC still represents a major therapeutic challenge. The review by Libe and colleagues provides an overview of current diagnosis and treatment of ACC, which emphasizes the need for novel therapeutic targets in a cancer with dismal prognosis. The review by Drougat and colleagues provides insight into the role of mutations targeting the WNT signaling pathway (essentially activating mutations of CTNNB1 and deletions of ZNRF3) and their pathogenic role in ACC. This paper on adult ACC is nicely complemented by Lalli and Figueiredo’s review that focuses on pediatric ACC. These are rare tumors that generally occur in the context of TP53 alterations, in particular the specific R337H mutation found with high frequency in Southern Brazil. The authors present evidence that these tumors are likely to derive from the fetal adrenal and discuss the common and divergent alterations found in pediatric and adult ACC, which highlights the lack of effective prognosis markers in the former. Deregulation of miRNA production is a common theme in most cancers. Nadia Cherradi provides a comprehensive overview of miRNA deregulation in ACC and shows that they can provide novel insight into the pathogenesis of ACC and may constitute interesting therapeutic targets. This review also highlights the usefulness of circulating miRNAs as novel non-invasive diagnostic and prognostic biomarkers in ACC. It further elaborates on an exciting aspect of miRNAs biology that involves their circulation within ACC cell-derived exosomes, which would allow communication with tumor microenvironment. We hope that you will find this topic inspiring and that it will shed light on exciting aspects of adrenal physiology and disease.