Familial Hyperaldosteronism Type 3 with a Rapidly Growing Adrenal Tumor: An In Situ Aldosterone Imaging Study

Primary aldosteronism is most often caused by aldosterone-producing adenoma (APA) and bi-lateral adrenal hyperplasia. Most APAs are caused by somatic mutations of various ion channels and pumps, the most common being the inward-rectifying potassium channel KCNJ5. Germ line mutations of KCNJ5 cause familial hyperaldosteronism type 3 (FH3), which is associated with severe hyperaldosteronism and hypertension. We present an unusual case of FH3 in a young woman, first diagnosed with primary aldosteronism at the age of 6 years, with bilateral adrenal hyperplasia, who underwent unilateral adrenalectomy (left adrenal) to alleviate hyperaldosteronism. However, her hyperaldosteronism persisted. At the age of 26 years, tomography of the remaining adrenal revealed two different adrenal tumors, one of which grew substantially in 4 months; therefore, the adrenal gland was removed. A comprehensive histological, immunohistochemical, and molecular evaluation of various sections of the adrenal gland and in situ visualization of aldosterone, using matrix-assisted laser desorption/ionization imaging mass spectrometry, was performed. Aldosterone synthase (CYP11B2) immunoreactivity was observed in the tumors and adrenal gland. The larger tumor also harbored a somatic β-catenin activating mutation. Aldosterone visualized in situ was only found in the subcapsular regions of the adrenal and not in the tumors. Collectively, this case of FH3 presented unusual tumor development and histological/molecular findings.

Feasibility of Imaging-Guided Adrenalectomy in Young Patients With Primary Aldosteronism

Many of the patients with primary aldosteronism (PA) are denied curative adrenalectomy because of limited availability or failure of adrenal vein sampling. It has been suggested that adrenal vein sampling can be omitted in young patients with a unilateral adrenal nodule, who show a florid biochemical PA phenotype. As this suggestion was based on a very low quality of evidence, we tested the applicability and accuracy of imaging, performed by computed tomography and/or magnetic resonance, for identification of unilateral PA, as determined by biochemical and/or clinical cure after unilateral adrenalectomy. Among 1625 patients with PA submitted to adrenal vein sampling in a multicenter multiethnic international study, 473 were ≤45 years of age; 231 of them had exhaustive imaging and follow-up data. Fifty-three percentage had a unilateral adrenal nodule, 43% had no nodules, and 4% bilateral nodules. Fifty-six percentage (n=131) received adrenalectomy and 128 were unambiguously diagnosed as unilateral PA. A unilateral adrenal nodule on imaging and hypokalemia were the strongest predictors of unilateral PA at regression analysis. Accordingly, imaging allowed correct identification of the responsible adrenal in 95% of the adrenalectomized patients with a unilateral nodule. The rate raised to 100% in the patients with hypokalemia, who comprised 29% of the total, but fell to 88% in those without hypokalemia. Therefore, a unilateral nodule and hypokalemia could be used to identify unilateral PA in patients ≤45 years of age if adrenal vein sampling is not easily available. However, adrenal vein sampling remains indispensable in 71% of the young patients, who showed no nodules/bilateral nodules at imaging and/or no hypokalemia. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01234220.

Эндогенный гиперкортизолизм: достижения и перспективы в диагностике и лечении

The results of examination and treatment of 647 patients with endogenous hypercortisolism were studied: pituitary corticotropinoma was detected in 494 (76.4%) patients, corticosteroma and pre corticosteroma of the adrenal gland in 142 (21.9%), bilateral macro-nodular hyperplasia of the adrenal glands of primary adrenal origin-in 11 (1.7%). Differential diagnosis of clinical forms of endogenous hypercortisolism was based on the assessment of the level of adrenocorticotropic hormone and cortisol, both in peripheral blood, and with selective bilateral blood sampling from the adrenal veins and lower stony sinuses, and the study of the nature of samples with 8 mg of dexamethasone. Topical diagnostics consisted in assessing the state of the adrenal glands and pituitary gland during computed tomography and magnetic resonance imaging with the use of contrast agents, and the use of special software 3D-Volume Rendering Technique allowed optimizing tactical and technical approaches to performing surgical interventions. Of the operated patients with adrenocorticotropic hormone dependent endogenous hypercortisolism, total removal according to the control magnetic resonance imaging was achieved in 92.3% of cases, subtotal in 7.7%. However, hormonal remission was achieved only in 82.4% of cases. All patients with corticosteroma and pre-corticosteroma of the adrenal gland underwent adrenalectomy: in 6 patients by open method, in 136 patients by endovideosurgical method (in 11 patients by laparoscopic method, in 124 patients by retroperitoneoscopic method, and in 1 patient by thoracoscopic transdiaphragmatic adrenalectomy). In all patients, the operation led to recovery. Patients with benign macronodular hyperplasia of the adrenal glands needed conservative treatment with steroidogenesis blockers. Indications for surgical treatment in the volume of unilateral adrenalectomy occurred only in 2 patients.

Aldosterone-producing nodules and CYP11B1 signaling correlate in primary aldosteronism

Autonomous cortisol secretion (ACS) could be found in some patients with unilateral primary aldosteronism (uPA). However, the histopathological patterns of uPA with concurrent ACS has not been well elucidated. The adrenal gland with the adenoma from 61 uPA patients who underwent unilateral adrenalectomy were assessed by immunohistochemistry. Bioinformatics analysis, including the Cancer Genome Atlas (TCGA) and Kyoto Encyclopedia of Genes and Genomes (KEGG), was applied. The prevalence of multiple aldosterone-producing nodules or micronodules (mAPN/mAPM) was 65.6% (40/61) among our uPA patients. Concurrent ACS was identified in 32% of this uPA cohort; they were associated with the interaction of larger tumor size (> 1.98 cm) and mAPN/mAPM (OR= 3.08, p= 0.004). Transcriptome analysis uncovered a dominant enrichment of HSD3B7 over-expression (p= 0.004) in the adenomas of the histopathologically classical adrenal uPA lesions with concomitant mAPN/mAPM, compared with those uPA adenomas without concurrent surrounding mAPN/mAPM. We identified a novel linkage of enhanced steroidogenic genes of HSD3B7 expression concurrent with downstream higher CYP11B1 expression; further relationship was confirmed by immunohistochemical staining and validated by TCGA bioinformatics. The presence of mAPN/mAPM in uPA patients had lower rate for biochemical success after adrenalectomy (p=0.047). In summary, two thirds of uPA patients had concomitant mAPN/mAPM; 1/3 of uPA patients had concurrent ACS. Steroidogenic HSD3B7/ CYP11B1 signaling was associated with uPA adenomas with surrounding mAPN/mAPM. Interaction of larger adenoma size with the presence of mAPN/mAPM was linked to co-existent ACS. Such uPA patients with concomitant mAPN/mAPM had lower rate of biochemical success.

Clinical and genetic heterogeneity of micronodular adrenal hyperplasia

Micronodular adrenal hyperplasia is a rare cause of ACTH-independent Cushing syndrome. It can be divided into two entities: primary pigmented nodular adrenocortical disease (PPNAD) and non-pigmented micronodular adrenocortical disease, among which familial and sporadic forms are distinguished. The most common is the genetically determined familial form PPNAD, as one of the components of Carney complex. The vast majority of patients have identifiable pathogenic variants in the PRKAR1A gene. In addition to the PRKAR1A gene mutations, inactivating mutations in the genes encoding phosphodiesterases (PDE11A4 and PDE8B), as well as PRKACA gene amplification, have been described in individuals with isolated forms. Despite the relative antiquity of the description of micronodular adrenal hyperplasia and the Carney comlex, a detailed study of pathophysiological mechanisms, genetic and clinical aspects of this pathology, nowadays, clinicians continue to face «atypical» cases. Thus, the nature of this disease is not well understood and requires further research. This review presents the accumulated data on micronodular adrenal hyperplasia, genetics aspects, and also describes 2 unique clinical cases of isolated PPNAD with unilateral adrenalectomy results.

Mitotane Treatment Combined With Unilateral Adrenalectomy in a Patient With Primary Pigmented Nodular Adrenocortical Disease Caused by a Start Codon Mutation of PRKAR1A Gene

Background: Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of Cushing’s syndrome (CS). This study aimed to explore molecular basis and treatment strategy in a patient with PPNAD.Methods: Whole-exome sequencing (WES) was used to reveal the mutation of PRKAR1A gene, with immunohistochemistry (IHC) to observe the expression of mutant PRKAR1A. Low-dose Mitotane followed by unilateral adrenalectomy were performed to control hypercortisolism. Results: A case of 45-year-old female present with classical hypercortisolism as excessive weight gain, central obesity, and intractable hypertension. She experienced adrenal adenoma surgery 10 years ago with no improvement. Low dosage of Mitotane was used for 7 months to control the severe hypercortisolism. Then laparoscopic unilateral adrenalectomy was performed and pathological features supporting PPNAD. The germline mutation (c.1A>G) in the start codon of PRKAR1A (Protein Kinase cAMP-Dependent Type I Regulatory Subunit Alpha) gene was identified. Notably, the body weight and hypertension were improved obviously one year later even if she discontinued with the Mitotane treatment.Conclusion: Low-dose Mitotane followed by unilateral adrenalectomy showed satisfied treatment effect in this patient, which may be an alternative treatment for PPNAD patient instead of bilateral adrenalectomy.

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.

Selective Glucocorticoid Replacement Following Unilateral Adrenalectomy for Hypercortisolism and Primary Aldosteronism

Background An institutional study previously demonstrated that cosyntropin stimulation testing on postoperative day 1 (POD1-CST) identified patients at risk for adrenal insufficiency (AI) following unilateral adrenalectomy (UA) for adrenal-dependent hypercortisolism (HC) and primary aldosteronism (PA), allowing for selective glucocorticoid replacement (GR). This study reevaluates the need for GR following UA for patients with HC and PA in a larger cohort. Methods A prospective database identified 108 patients who underwent UA for mild autonomous cortisol excess (MACE) (n=47), overt hypercortisolism (OH) (n=27), PA (n=22), and concurrent PA/HC (n=12) from 9/2014-10/2020; all underwent preoperative evaluation for HC. MACE was defined as 1mg dexamethasone suppression test (DST) cortisol >1.8 (μg/dL), with ≥5 defined as OH. GR was initiated for basal cortisol ≤5 or stimulated cortisol ≤14 (≤18 prior to 4/2017) on POD1-CST. Results Fifty-one (47%) patients had an abnormal POD1-CST; 54 (50%) were discharged on GR (27 MACE, 20 OH, 1 PA, 6 PA/HC). Median duration of GR was OH: 6.0 months, MACE: 2.1 months, PA: 1 month, PA/HC: 0.8 months. Overall, 26% (n=7) of OH patients and 43% (n=20) of MACE patients did not require GR. Two (2%) OH patients had normal POD1-CST but developed AI several weeks postoperatively requiring GR. None experienced life-threatening AI. Conclusion POD1-CST identifies HC patients at risk for AI after UA, allowing for selective GR. One-quarter of OH patients and nearly half of MACE patients can forego GR after UA. PA patients do not require evaluation for AI if concurrent HC has been excluded preoperatively.

Characteristics of a Novel ATP2B3 K416_F418delinsN Mutation in a Classical Aldosterone-Producing Adenoma

In patients with primary aldosteronism (PA), the prevalence of ATP2B3 mutation is rare. The aim of this study is to report a novel ATP2B3 mutation in a PA patient. Based on our tissue bank of aldosterone-producing adenomas (APA), we identified a novel somatic ATP2B3 K416_F418delinsN mutation. The affected individual was a 53 year-old man with a 4 year history of hypertension. Computed tomography (CT) showed bilateral adrenal masses of 1.6 (left) and 0.5 cm (right) in size. An adrenal venous sampling (AVS) showed a lateralization index (LI) of 2.2 and a contralateral suppression index (CLS) of 0.12; indicating left functional predominance. After a left unilateral adrenalectomy, he achieved partial biochemical and hypertension–remission. This classical adenoma harbored a novel ATP2B3 K416_F418delinsN somatic mutation, which is a deletion from nucleotides 1248 to 1253. The translated amino acid sequence from 416 to 418, reading as lysine-phenylalanine-phenylalanine, was deleted; however, an asparagine was inserted due to merging of residual nucleotide sequences. The CYP11B2 immunohistochemistry staining demonstrated strong immunoreactivity in this classical adenoma. The ATP2B3 K416_F418delinsN mutation is a functional mutation in APA, since HAC15 cells, a human adrenal cell line, transfected with the mutant gene showed increased CYP11B2 expression and aldosterone production.