Clinical and cardiac characteristics of primary bilateral macronodular adrenal hyperplasia.

Background: Cardiovascular disease is the leading cause of death in Cushingzs syndrome (CS). Primary bilateral macro-nodular adrenal hyperplasia (PBMAH), is a rare cause of CS that is clinically distinct from the other common types of CS, but cardiac characteristics have been poorly studied. Methods: The clinical data, steroid hormones and echocardiographic variables of 17 patients with PBMAH were collected. Twenty-one CS patients with cortisol-producing adenoma (CPA) were collected as controls. The similarities and differences of clinical and cardiac features between the two groups were compared.

Corticotropin-releasing hormone test predicts the outcome of unilateral adrenalectomy in primary bilateral macronodular adrenal hyperplasia.

PURPOSE: Primary bilateral adrenal hyperplasia (PBMAH) is associated with hypercortisolism and a heterogeneous clinical expression in terms of cortisol secretion and related comorbidities. Historically, treatment of choice was bilateral adrenalectomy (B-Adx); however, recent data suggest that unilateral adrenalectomy (U-Adx) may be an effective alternative. For the latter, factors predicting the postsurgical outcome (e.g., biochemical control) have not been identified yet. METHODS: PBMAH patients undergoing U-Adx for overt Cushing's syndrome (CS) in two tertiary care centers were retrospectively analysed. Remission was defined as a normalization of urinary free cortisol (UFC) without the need for medical treatment. The potential of hCRH test as a predictor of U-Adx outcome was evaluated in a subgroup. RESULTS: 23 patients were evaluated (69% females, mean age 55 years). Remission rate after U-Adx was 74% at last follow up (median 115 months from UAdx). Before U-Adx, a positive ACTH response to hCRH (Δ%ACTH increase > 50% from baseline) was associated with higher remission rates. CONCLUSIONS: Three of four patients with PBMAH are surgically cured with U-Adx. Pre-operative hCRH testing can be useful to predict long-term remission rates.

Unexpected exacerbation of cryptococcal meningitis after unilateral adrenalectomy in a PMAH patient: a case report and literature review.

BACKGROUND: Primary bilateral macronodular adrenal hyperplasia (PMAH) combined with infection by an opportunistic pathogen is complicated. Clinical evidence on managing PMAH patients with infections by opportunistic pathogens is insufficient. CASE PRESENTATION: A 66-year-old male was admitted with bilateral adrenal masses and was diagnosed with PMAH. Fever and disturbance of consciousness appeared after laparoscopic left adrenalectomy. Cryptococcal meningitis was confirmed by cerebrospinal fluid (CSF) culture. The exacerbation of his medical condition was suspected to result from immune reconstitution inflammatory syndrome (IRIS), and he had been treated with antifungal therapy and glucocorticoid replacement, but he responded poorly and eventually died of multiorgan failure. We summarized the clinical observations of 12 Cushing's syndrome (CS) patients infected by Cryptococcus. Seven out of nine patients who were treated for cryptococcus infection before receiving CS survived, while three patients treated for cryptococcus infection after CS treatment developed signs of IRIS and eventually died. CONCLUSION: Cushing's syndrome, complicated with cryptococcal infection, has a high mortality rate, mainly when IRIS emerges. Carefully identifying the presence of the suspected infection, and controlling cryptococcal infection before removing the culprit adrenals could be the rational choice.

Prevalence and clinical features of armadillo repeat-containing 5 mutations carriers in a single center cohort of patients with bilateral adrenal incidentalomas.

OBJECTIVE: We aimed to evaluate the prevalence of armadillo repeat-containing 5 (ARMC5) genetic defects in our cohort of bilateral adrenal incidentaloma (BAI) patients and to evaluate the possible existence of genotype-phenotype correlations. DESIGN: Cross-sectional study. SETTING: Tertiary care center. PARTICIPANTS: 72 BAI patients. MAIN OUTCOME MEASURE(S): The following data have been collected: morning adrenocorticotropic hormone (ACTH) concentrations; cortisol levels after 1 mg overnight dexamethasone suppression test (F-1mgDST); urinary free cortisol (UFC) levels; diameter of the adrenal masses; and the association with overweight/obesity, arterial hypertension, diabetes mellitus, dyslipidemia, cardiovascular events, unrelated neoplasia, osteoporosis, thyroid nodular disease, and primary hyperparathyroidism. A search for ARMC5 germline and somatic pathogenic variants was performed in all patients and in the adrenal tissue of patients operated on, respectively. RESULTS: The prevalence of germline ARMC5 pathogenic variants among patients with mild autonomous cortisol secretion (MACS+, defined as F-1mgDST > 1.8 µg/dL) was 18.8%. No germline pathogenic variants were detected in patients without MACS. Moreover, somatic ARMC5 pathogenic variants were also found in the adrenal tissue of six patients without germline ARMC5 variants. The F-1mgDST levels >5 µg/dL predicted with a poor sensitivity but a 90.5% specificity in identifying the presence of ARMC5 germline pathogenic variants. We did not find any clinical parameter predictive of the ARMC5 mutation presence. CONCLUSIONS: In MACS+ BAI patients, germline ARMC5 gene pathogenic variants are frequent. Further studies are needed to elucidate the pathophysiological role of somatic ARMC5 pathogenic variants on adrenal tumor development in otherwise wild-type (WT) patients.

[Macronodular adrenal hyperplasia causing Cushing's syndrome due to ARMC5 gene mutation.] / Cushing-szindrómát okozó macronodularis mellékvese-hyperplasia ARMC5-génmutáció következtében.

Our 69-year-old female patient was investigated for a 20 kg weight gain over 2 years. The patient's medical history included hypertension, hyperuricemia, bilateral cataract surgery and musculosceletal complaints. Diabetes mellitus was not found. Physical examination revealed abdominal obesity, proximal myopathy and atrophic, vulnerable skin. The "overnight", low-dose and long, low-dose dexamethasone suppression tests indicated autonomous cortisol overproduction (plasma cortisol level: 172.6 and 153.2 nmol/L, cut-off: 50 nmol/L). The suppressed ACTH (<1.11 pmol/L, normal value: 1.12-10.75 pmol/L) suggested ACTH-independent hypercortisolism. Abdominal CT described macronodular enlargement of both adrenals. The size of the largest nodule was 23 × 20 mm in the right, and 24 × 30 mm on the left side (with -33 ± 37 HU density values on native scans). The 131I-cholesterol adrenal scintigraphy and SPECT/CT showed almost equally intensive radiopharmacon uptake on both sides. Based on the clinical results, bilateral macronodular adrenal hyperplasia associated with ACTH-independent hypercortisolism was diagnosed. Genomic DNA was obtained from the peripheral blood leukocytes. Targeted sequencing of 25 genes potentially involved in adrenal tumorigenesis revealed a new disease-causing armadillo repeat-containing 5 (ARMC5) gene mutation (c.1724del28 bp, g.31,476,067-31,476,094). Because of the autosomal dominant inheritance of this genetic alteration, the patient's two children underwent genetic screening for the ARMC5 mutation. The same mutation was found in the younger child of our patient. To the best of our knowledge, this is the first published Hungarian case of ARMC5 mutation with bilateral macronodular adrenal hyperplasia and ACTH-independent Cushing's syndrome. The genetic alteration is present in two generations of the family of the index patient. Orv Hetil. 2023; 164(32): 1271-1277.

Primary bilateral macronodular adrenal hyperplasia: A series of 32 cases and literature review.

Primary bilateral macronodular adrenal hyperplasia (PBMAH) accounts for <2% of cases of Cushing's syndrome. The majority of patients present with no obvious steroid excess it means with autonomous cortisol secretion (ACS). The classic treatment for patients with overt Cushing's syndrome is bilateral adrenalectomy, but unilateral resection of the larger adrenal gland can result in clinical and/or biochemical remission in >90% of cases, especially in cases of ACS. In this article, a series of 32 cases with PBMAH is described. Most of the cases of PBMAH had ACS, except for one case with overt Cushing's syndrome. A study of aberrant receptors was performed in six patients, being negative in three cases, positive in the metoclopramide test in two cases and positive in the metoclopramide test and in the mixed meal test in another patient. The patient with overt Cushing's syndrome was treated with adrenostatic therapy achieving biochemical control, while two patients with ACS underwent unilateral adrenalectomy with resection of the largest adrenal gland, demonstrating hypercortisolism remission and improvement of cardiovascular risk factors after surgery. This article describes a series of 32 cases of PBMAH and offers a comprehensive review of PBMAH.

Extensive expertise in endocrinology: glucose-dependent insulinotropic peptide-dependent Cushing's syndrome.

Thirty years ago, we identified that cortisol secretion in some patients with unilateral adenoma or primary bilateral macronodular adrenal hyperplasia (PBMAH) was stimulated by food intake; this was secondary to the abnormal adrenocortical responsiveness to physiological post-prandial increase in glucose-dependent insulinotropic peptide (GIP). This resulted from the ectopic expression of non-mutated GIP receptor in the pathological adrenal tissues of those patients. Although ectopic GIP receptor (GIPR) was confirmed in a relatively limited number of cases to date, its elucidation leads to the identification of a wide diversity of aberrant G-protein-coupled receptors regulating steroidogenesis and cell proliferation in a high proportion of patients with PBMAH or cortisol-secreting adenomas. In addition, ectopic GIPR was identified in other endocrine tumors including somatotroph pituitary tumors with paradoxical growth hormone response to oral glucose, medullary thyroid carcinomas, and other neuroendocrine tumors. The first molecular pathogenic mechanism responsible for ectopic GIPR expression was elucidated in unilateral GIP-dependent adenomas in which somatic duplication and rearrangements in chromosome region 19q13.32 containing the GIPR locus lead to increased expression of GIPR which was enhanced by the activity of a glucocorticoid response element. Recently, germline lysine demythylase 1A (KDMIA) mutations combined with somatic chromosome 1p deletions were found to be specifically responsible for ectopic GIPR in sporadic or familial GIP-dependent PBMAH and can be associated with adrenal myelolipoma, monoclonal gammopathy of unknown significance (MGUS), or multiple myeloma. Screening for ectopic GIPR should be conducted in all patients with PBMAH; genetic studies to identify KDM1A mutations should be offered to such patients in order to detect affected members and provide early detection of PBMAH and other potential associated neoplasias. The elucidation of GIP-dependent Cushing's syndrome (CS) illustrates that careful bedside phenotyping of rare conditions can lead to identification of genetically determined diseases requiring personalized approaches to investigation and therapy.

The effect of unilateral adrenalectomy on patients with primary bilateral macronodular adrenal hyperplasia.

PURPOSE: To evaluate the long-term effect of unilateral adrenalectomy (uADX) on patients with primary bilateral macronodular adrenal hyperplasia (PBMAH). METHODS: We retrospectively reviewed 29 patients (including 11 men and 18 women) with PBMAH and Cushing's syndrome (CS) between 2005 and 2019 who underwent uADX in our center. Clinical symptoms, serum cortisol (8:00 a.m., 4:00 p.m., and 0:00 a.m.), 24 h urinary free cortisol (UFC), computed tomography (CT) scan of the adrenal gland, and pituitary nuclear magnetic resonance (MR) scan performed before and after operation were analyzed. RESULTS: The median follow-up time was 39 (13-134) months. uADX decreased significantly at 24 h UFC (median: 357.14 vs. 89.50 ug/24 h, P < 0.001) and serum cortisol (8:00 a.m.) (median: 22.88 vs. 12.50 ug/uL, P < 0.001) 1 year after surgery. In total, 17 of 29 patients had normal UFC again 1 year after surgery, while one of them suffered a relapse after 61 months. However, uADX failed to decrease UFC to the normal range in the other patients. Ten of the remaining 12 uncured patients and the relapsed patient finally underwent contralateral adrenalectomy (cADX). The 24 h UFC of the patients who were cured (n = 17) after uADX was significantly lower than that of the uncured patients (n = 12) (222.30 vs. 579.10 ug/24 h, P = 0.011). CONCLUSION: uADX may be an appropriate treatment for patients with mildly elevated cortisol, while contralateral adrenalectomy (cADX) may be required for patients with highly elevated cortisol. The level of 24 h UFC is helpful to predict patients' prognosis.

Single-center experience with vascularized adrenal displacement for the treatment of primary bilateral macronodular adrenal hyperplasia / 现代泌尿外科杂志

【Objective】 To explore a new treatment of primary bilateral macronodular adrenal hyperplasia (PBMAH) and its efficacy. 【Methods】 Clinical data of 20 PBMAH patients treated in our hospital during Mar.2010 and Apr.2021 were retrospectively analyzed. All patients underwent laparoscopic subcutaneous displacement of vascularized adrenal. The clinical symptoms, plasma free cortisol, adrenocorticotrophic hormone (ACTH), and 24 h urinary free cortisol were regularly monitored after surgery. 【Results】 Of all 20 patients, 19 were followed up for 18 to 120 months (median 60 months). Three months after surgery, reexamination showed 1 patient had decreased plasma free cortisol and increased ACTH, but had no symptoms of low corticosteroids. After another 3 months, the plasma free cortisol and ACTH returned to normal. After 4 to 48 months, the parameters recovered in all patients and the clinical symptoms disappeared. 【Conclusion】 Laparoscopic vascularized adrenal displacement is a new and effective method for the treatment of PBMAH. It can alleviate the Cushing syndrome with no obvious adverse reactions.

Prevalencia y fenotipo de la hiperplasia suprarrenal macronodular bilateral primaria con secreción autónoma de cortisol: un estudio de 98 pacientes / Prevalence and phenotype of primary bilateral macronodular adrenal hyperplasia with autonomous cortisol secretion: a study of 98 patients

Objetivo Se evaluó la prevalencia de hiperplasia suprarrenal macronodular bilateral primaria (PBMAH). También se analizó el fenotipo diferencial de los pacientes con PBMAH en comparación con otras lesiones suprarrenales bilaterales que no cumplían con la definición de PBMAH. Métodos Revisamos las historias clínicas de 732 pacientes diagnosticados de incidentaloma suprarrenal en nuestro centro. Se incluyeron 98 pacientes con hipercortisolismo subclínico para el análisis. Se definió PBMAH como la presencia de cortisol plasmático > 1,8 μg/dL después de una prueba de 1 mg de dexametasona durante la noche, hiperplasia suprarrenal bilateral y nódulos suprarrenales bilaterales > 1 cm. Resultados Un total de 31 pacientes tenían PBMAH. Los pacientes con PBMAH mostraron una mayor prevalencia de secreción autónoma de cortisol (cortisol plasmático > 5,0 μg/dL después de la prueba de 1 mg de dexametasona durante la noche) que los pacientes sin PBMAH (OR 4,1, IC del 95%: 1,38-12,09, p = 0,010). El tamaño del tumor y la masa adenomatosa total fueron significativamente mayores en pacientes con PBMAH en comparación con los pacientes sin PBMAH (30,2 ± 12,16 vs. 24,3 ± 8,47 mm, p = 0,010 y 53,9 ± 20,8 vs. 43,3 ± 14,62 mm, p = 0,023), respectivamente. Una mayor proporción de pacientes con PBMAH tenían diabetes en comparación con los pacientes sin PBMAH (45,2% vs. 25,4%, p = 0,05). Conclusión PBMAH está presente en un tercio de los pacientes con incidentaloma suprarrenal e hipercortisolismo subclínico. Los pacientes con PBMAH mostraron una mayor secreción autónoma de cortisol, mayor tamaño del tumor y diabetes que aquellos sin PBMAH (AU)

Aim This study evaluated prevalence of primary bilateral macronodular adrenal hyperplasia (PBMAH). It also analyzed the differential phenotype of patients with PBMAH compared to other bilateral adrenal lesions that do not meet the definition of PBMAH. Methods We reviewed the medical records of 732 patients diagnosed with an adrenal incidentaloma at our center. Ninety-eight patients with subclinical hypercortisolism were included in the analysis. We defined PBMAH as the presence of plasma cortisol > 1.8 μg/dL after an over-night 1-mg dexamethasone test, bilateral adrenal hyperplasia, and bilateral adrenal nodules > 1 cm. Results A total of 31 patients had PBMAH. Patients with PBMAH showed greater prevalence of autonomous cortisol secretion (plasma cortisol > 5.0 μg/dL after an overnight 1-mg dexamethasone test) than patients without PBMAH (OR 4.1, 95%CI 1.38-12.09, p = 0.010). Tumor size and total adenomatous mass were significantly greater in patients with PBMAH compared to patients without PBMAH (30.2 ± 12.16 vs. 24.3 ± 8.47 mm, p = 0.010 and 53.9 ± 20.8 vs. 43.3 ± 14.62 mm, p = 0.023), respectively. A greater proportion of patients with PBMAH had diabetes compared to patients without PBMAH (45.2% vs. 25.4%, p = 0.05). Conclusion PBMAH is present in one-third of patients with adrenal incidentaloma and subclinical hypercortisolism. Patients with PBMAH showed greater autonomous cortisol secretion, bigger tumor size, and higher rates of diabetes than those without PBMAH (AU)

A novel pathogenic variant of ARMC5 in a patient with primary bilateral macronodular adrenal hyperplasia: a case report.

BACKGROUND: Primary bilateral macronodular adrenal hyperplasia (PBMAH), also known as adrenocorticotropic hormone (ACTH)-independent macronodular adrenal hyperplasia, is a rare cause of endogenous Cushing's syndrome. In many familial cases of PBMAH, the variants in armadillo repeat containing 5 (ARMC5) gene are found to be associated with the disease. Here, we report a case of PBMAH harboring a novel frameshift variant in ARMC5 gene, which has not been previously reported in the literature. CASE PRESENTATION: A 67-year-old woman was referred due to the clinical features of Cushing's syndrome. Radiological imaging and hormonal testing were carried out. The serum levels of cortisol were remarkably increased at late night and did not suppress even after 1 mg of dexamethasone administration, while the plasma levels of ACTH hormone were decreased significantly. The patient underwent unilateral left-sided laparoscopic adrenalectomy, and the diagnosis of PBMAH was substantiated by histopathological analysis. Moreover, the partial envelope was incomplete and the cell proliferation index was low. Specifically, inhibin α-subunit ( +), syn focal ( +), Ki-67 ~ 3% ( +), CgA (-) and CEA (-) were observed. DNA sequencing data revealed that a novel frameshift variant (c.363_373delGCCAGTGCGCC, p.Pro122Alafs*61) was identified in ARMC5 gene. However, this variant was not detected in the daughter of the patient. The rest of the family members, including her sister, son and two brothers, were not consented for genetic testing. CONCLUSIONS: Early detection of ARMC5 variant status and familial screening might have important clinical implications for the diagnosis and prognosis of PBMAH patients. A novel ARMC5 frameshift variant (c.363_373delGCCAGTGCGCC, p.Pro122Alafs*61) was identified to be associated with the pathogenesis of PBMAH. ARMC5 sequencing may improve the identification of a causative gene variant for PBMAH and allow earlier diagnosis of this disease.

Decreased steroidogenic enzyme activity in benign adrenocortical tumors is more pronounced in bilateral lesions as determined by steroid profiling in LC-MS/MS during ACTH stimulation test.

Objective: Large response of steroid precursors, including 17-hydroxyprogesterone, to adrenocorticotropic hormone (ACTH) has been described in adrenocortical tumors, suggesting the existence of intra-tumoral enzymatic deficiencies. This study aimed to compare steroidogenesis enzymes activity in unilateral and bilateral benign tumors using serum steroid profiling in liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) in the basal state and after ACTH 1-24 stimulation. Design and methods: A serum profile of seven consecutive adrenal steroids was determined in LC-MS/MS in the basal state (T0) and after ACTH 1-24 stimulation (T60) in 35 patients with bilateral adrenocortical tumors (BL), 38 patients with unilateral tumors (UL) and 37 control subjects (CT). Response amplitude of each individual steroid was evaluated by T60/T0 ratio, whereas enzymatic activity was assessed by the downstream/upstream steroid ratio. Adrenal volume was quantified by a semi-automatic segmentation method. Results: For the seven steroids assayed, the amplitude of response to ACTH was higher in BL than in UL and in CT. The difference between BL and UL persisted even after matching patients on adrenal volume. On glucocorticoids pathway, enzymatic activity of CYP11B1 was significantly decreased in BL (78.3 (43.1-199.4)) in comparison to both UL (122.7 (13.8-228.4), P = 0.0002) and CT (186.8 (42.1-1236.3), P < 0.0001). On mineralocorticoids and androgens pathways, the enzymatic activity of CYP11B2 and CYP17A1-17,20 lyase was also lower in BL than UL and CT. Conclusions: Decreased activity of distal steroidogenesis enzymes CYP11B1, CYP11B2 and CYP17A1-17,20 lyase, responsible for an explosive response to ACTH of upstream precursors in bilateral tumors, limits the synthesis of bioactive steroids, in particular cortisol, despite the increase in adrenal mass. Significance statement: Activity of distal steroidogenesis enzymes (CYP11B1, CYP11B2 and CYP17A1 on glucocorticoids, mineralocorticoids and androgens pathways, respectively) is decreased in adrenocortical benign tumors. This decrease is more pronounced in bilateral lesions and seems to depend more on the nature of the lesion than on the increase in adrenal volume. It is responsible for the explosive response to ACTH of steroid precursors located upstream of these enzymes. It probably allows bioactive steroids, particularly cortisol, to stay in the normal range for a long time despite the increase in adrenal mass.

Prevalence and phenotype of primary bilateral macronodular adrenal hyperplasia with autonomous cortisol secretion: a study of 98 patients.

AIM: This study evaluated prevalence of primary bilateral macronodular adrenal hyperplasia (PBMAH). It also analyzed the differential phenotype of patients with PBMAH compared to other bilateral adrenal lesions that do not meet the definition of PBMAH. METHODS: We reviewed the medical records of 732 patients diagnosed with an adrenal incidentaloma at our center. Ninety-eight patients with subclinical hypercortisolism were included in the analysis. We defined PBMAH as the presence of plasma cortisol > 1.8 µg/dL after an over-night 1-mg dexamethasone test, bilateral adrenal hyperplasia, and bilateral adrenal nodules > 1 cm. RESULTS: A total of 31 patients had PBMAH. Patients with PBMAH showed greater prevalence of autonomous cortisol secretion (plasma cortisol > 5.0 µg/dL after an overnight 1-mg dexamethasone test) than patients without PBMAH (OR 4.1, 95%CI 1.38-12.09, p = 0.010). Tumor size and total adenomatous mass were significantly greater in patients with PBMAH compared to patients without PBMAH (30.2 ±â€¯12.16 vs. 24.3 ±â€¯8.47 mm, p = 0.010 and 53.9 ±â€¯20.8 vs. 43.3 ±â€¯14.62 mm, p = 0.023), respectively. A greater proportion of patients with PBMAH had diabetes compared to patients without PBMAH (45.2% vs. 25.4%, p = 0.05). CONCLUSION: PBMAH is present in one-third of patients with adrenal incidentaloma and subclinical hypercortisolism. Patients with PBMAH showed greater autonomous cortisol secretion, bigger tumor size, and higher rates of diabetes than those without PBMAH.

A 30-Year, Single-Center Experience of Unilateral Adrenalectomy for Primary Bilateral Macronodular Adrenal Hyperplasia.

OBJECTIVE: The aim was to assess the short- and long-term outcomes of unilateral adrenalectomy (UA) in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH). METHODS: We conducted a retrospective study of 124 patients with PBMAH who underwent UA. RESULTS: One hundred sixteen patients were available for follow-up (median, 28.5 months). Cushingoid features remitted in 43 of 65 patients (70.8%) with overt Cushing syndrome (CS). Hypertension and diabetes mellitus improved in 79 of 96 (82.3%) and 29 of 42 patients (69.0%), respectively. Glucocorticoid insufficiency developed in 7 of 116 patients (6.0%) after the surgery, and it resolved in all the patients during follow-up. The mean 24-hour urinary free cortisol level decreased gradually from 456.02 ± 422.33 mg/24 h at baseline to 84.47 ± 70.06 mg/24 h within 3 months and then increased progressively in some patients. Sixty-four of the 116 patients (55.2%) had biochemical recurrence and 43 patients (67.2%) underwent contralateral adrenalectomy. The median time interval between the second operation and the first UA was 24 months. Patients with overt CS had a larger surgical-side or contralateral adrenal volume than patients without overt CS. Patients with a contralateral adrenal volume of >33.54 mL or with a preoperative urinary free cortisol level of >216.08 mg/24 h were more likely to have recurrence. CONCLUSION: The efficiency of UA is transient for the majority of patients, and the indications should be strictly limited to those with subclinical or milder CS. Patients who undergo successful UA still require close life-time follow-up for the recurrence of hypercortisolism.

Bilateral Adrenal Hyperplasia: Pathogenesis and Treatment.

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.

Unilateral adrenalectomy partially improved hyperglycemia in a patient with primary bilateral macronodular adrenal hyperplasia.

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 131I-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.

Role of unilateral adrenalectomy in bilateral adrenal hyperplasias with Cushing's syndrome.

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.

Update on primary bilateral macronodular adrenal hyperplasia (PBMAH).

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.

Adrenocortical hyperplasia: A multifaceted disease.

Adrenocortical hyperplasia may develop in different contexts. Primary adrenal hyperplasia may be secondary to primary bilateral macronodular adrenocortical hyperplasia (PBMAH) or micronodular bilateral adrenal hyperplasia (MiBAH) which may be divided in primary pigmented nodular adrenocortical disease (PPNAD) and isolated micronodular adrenocortical disease (i-MAD). Both lead to oversecretion of cortisol and potentially to Cushing's syndrome. Moreover, adrenocortical hyperplasia may be secondary to longstanding ACTH stimulation in ACTH oversecretion as in Cushing's disease, ectopic ACTH secretion or glucocorticoid resistance syndrome and congenital adrenal hyperplasia secondary to various enzymatic defects within the cortex. Finally, idiopathic bilateral adrenal hyperplasia is the most common cause of primary aldosteronism. We will discuss recent findings on the multifaceted forms of adrenocortical hyperplasia.

[Hereditary Cushing's syndrome caused by primary bilateral macronodular adrenal hyperplasia due to ARMC5 mutation with concomitant primary hyperparathyroidism: the first known case in Russia].

Primary bilateral macronodular adrenal hyperplasia (PBMAH), a genetically heterogeneous disease, is a rare cause of Cushing's syndrome. Until recently, few cases were attributed to mutations in known genes. However, in 2013, ARMC5, a newly discovered tumor suppressor gene, was identified. Further studies have shown that mutations in the ARMC5 gene are found in 25-55% of all PBMAH cases. This article describes a clinical case of hereditary Cushing's syndrome caused by PBMAH in a 37-year old patient. The patient's family history is remarkable for the presence of Cushing's syndrome and PBMAH in the patient's mother. Bilateral adrenalectomy was performed as the treatment of choice. Genetic analysis using whole-exome sequencing confirmed the hereditary cause of the disease, revealing a germline heterozygous mutation in the ARMC5 gene. The patient also had concomitant mild primary hyperparathyroidism, which had not been observed before in genetic carriers with the ARMC5 mutation.