ENDOCRINE SOCIETY
OXFORD
Genetic Dissection of Primary Aldosteronism in a Patient With MEN1 and Ipsilateral Adrenocortical Carcinoma and Adenoma
Stefanie Parisien-La Salle, 10D Gilles Corbeil,1 Zaki El-Haffaf,2 Caroline Duranceau,3 Mathieu Latour,4 Pierre I. Karakiewicz,5 Andre Lacroix,10D and Isabelle Bourdeau1(D
1Division of Endocrinology, Department of Medicine, Research Center, Centre hospitalier de l’Université de Montréal (CHUM), Montreal, QC, H2X 0C1, Canada
2Division of Genetics, Department of Medicine, Research Center, Centre hospitalier de l’Université de Montréal (CHUM), Montreal, QC, H2X 0C1, Canada
3Division of Endocrinology, Department of Medicine, Chicoutimi Hospital, Université du Québec à Chicoutimi, Chicoutimi, QC, H2X OC1, Canada
4Department of Pathology and Cellular Biology, Centre hospitalier de l’Université de Montréal (CHUM), Montreal, QC, H2X 0C1, Canada
5Division of Urology, Department of Surgery, Centre Hospitalier de l’Université de Montréal, Montréal, QC, H2X 0C1, Canada
Correspondence: Isabelle Bourdeau, MD, Division of Endocrinology, Department of Medicine, CRCHUM, 900 rue Saint-Denis, Tour Viger-R, Bureau R08.470, Montréal, QC, H2X 0A9, Canada. Email: isabelle.bourdeau@umontreal.ca.
Abstract
Background: Adrenal tumors are found in up to 40% of patients with multiple endocrine neoplasia type 1 (MEN1). However, adrenocortical carcinomas (ACC) and primary aldosteronism (PA) are rare in MEN1.
Case: A 48-year-old woman known to have primary hyperparathyroidism and hypertension with hypokalemia was referred for a right complex 8-cm adrenal mass with a 38.1 SUVmax uptake on 18F-FDG PET/CT. PA was confirmed by saline suppression test (aldosterone 1948 pmol/L- 1675 pmol/L; normal range [N]: < 165 post saline infusion) and suppressed renin levels (<5 ng/L; N: 5-20). Catecholamines, androgens, 24- hour urinary cortisol, and pituitary panel were normal. A right open adrenalectomy revealed a concomitant 4-cm oncocytic ACC and a 2.3-cm adrenocortical adenoma. Immunohistochemistry showed high expression of aldosterone synthase protein in the adenoma but not in the ACC, supporting excess aldosterone production by the adenoma.
Genetic analysis: After genetic counseling, the patient underwent genetic analysis of leucocyte and tumoral DNA. Sequencing of MEN1 revealed a heterozygous germline pathogenic variant in MEN1 (c.1556delC, p.Pro519Leufs*40). The wild-type MEN1 allele was lost in the tumoral DNA of both the resected adenoma and carcinoma. Sequencing analysis of driver genes in PA revealed a somatic pathogenic variant in exon 2 of the KCNJ5 gene (c.451G>A, p.Gly151Arg) only in the aldosteronoma.
Conclusion: To our knowledge, we describe the first case of adrenal collision tumors in a patient carrying a germline pathogenic variant of the MEN1 gene associated with MEN1 loss of heterozygosity in both oncocytic ACC and adenoma and a somatic KCNJ5 pathogenic variant leading to aldosterone-producing adenoma. This case gives new insights on adrenal tumorigenesis in MEN1 patients.
Key Words: MEN1, oncocytic adrenocortical carcinoma, primary aldosteronism, genetics
Abbreviations: ACC, adrenocortical carcinomas; ACT, adrenal collision tumors; APAs, aldosterone-producing adenomas; CT, computed tomography; 18F-FDG PET/CT, 18F-fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography; LOH, loss of heterozygosity; MEN1, multiple endocrine neoplasia type 1; PA, primary aldosteronism.
MEN1 (multiple endocrine neoplasia type 1) is an autosomal dominant genetic disease with an incidence of 0.25% in post- mortem studies (1). Cardinal features include primary hyper- parathyroidism (90%), neuroendocrine tumors (30%-70%) and pituitary adenomas (30%-40%). Adrenal tumors are also a frequent occurrence in MEN1 patients with an inci- dence of 20%-73% (1). Adrenal involvement includes hyper- plasia, adenomas, carcinomas, and cysts, but fewer than 10% of these patients have hormonal hypersecretion (1).
Although primary aldosteronism (PA) is a frequent cause of secondary hypertension, it can rarely be found in a syndromic presentation, such as in patients with MEN1 (2, 3). The
prevalence of PA ranges from 3.2% to 7.2% in mild to mod- erate hypertension and can reach more than 20% in resistant hypertension or in patients with sleep apnea and atrial fibrilla- tion (4). Prevalence of PA in MEN1 with adrenal involvement is approximately 2.3% to 2.7% (2, 5). Although most cases of PA are sporadic, genetic evaluation can be warranted in younger patients and patients with a familial history of PA for identification of germline mutations in familial forms of hyperaldosteronism (3, 6). Somatic mutations also play an important role in the pathogenesis of sporadic PA. KCNJ5 (potassium channel kir3.4) is frequently mutated in aldosterone-producing adenomas (APAs) (7). A somatic
A
B
mutation in this gene is present in up to 40% of patients with PA in the European population and this prevalence almost doubles in the Asian populations (7-13). Other driver genes involved in PA include the CACNA1D, CACNA1H, CLCN2, ATP2B3, and ATP1A1 genes (14-18).
Adrenal implication of MEN1 syndrome can also include adrenocortical carcinomas (ACC) (2). In a series of 715 pa- tients with MEN1, 8 patients presented with ACCs (1.12%) (2). A thorough review of the literature by Want et al (5) in- cluded 9 studies of patients with MEN1 to calculate the preva- lence of ACCs and they revealed a pooled prevalence of 18/1187 (1.5%).
We report here the case of a patient with MEN1 with sim- ultaneous ipsilateral ACC and APA with a somatic pathogenic variant in KCNJ5 in the adenoma.
Case Description
We report the case of a 48-year-old woman, who was admit- ted to our center for a right adrenalectomy. Her past medical history included primary hyperparathyroidism and uterine fi- bromas. She also reported a 3-year history of hypertension with hypokalemia (K: 2.9 mmol/L) controlled with dual anti- hypertensive therapy. Her father had a gastrinoma (Zollinger- Ellison syndrome). She was first diagnosed with primary hyperparathyroidism with calcium levels of 2.75 mmol/L (normal range [N]: 2.17-2.56 mmol/L), PTH levels of 13.4 pmol/L (N: 1.4-6.8 pmol/L), elevated 24-hour calciuria (FeCa: 1.93%), and vitamin D of 65.7 U/L (N: 75-125 U/L); a MIBG parathyroid scan showed no focal uptake. A MEN1 syndrome was suspected and an initial neuroendocrine work- up including an abdominal or abdomino-pelvic computed tomography (CT) scan with contrast showed a complex 8 cm right adrenal mass (4 cm cystic and 4 cm solid) and a 1.8 cm left adrenal nodule. Due to the size of the lesion and suspicion for malignancy, a 18F-fluoro-2-deoxy-D-glucose positron emission tomography-CT (18F-FDG PET/CT) was ordered. On 18F-FDG PET/CT, the right adrenal mass had an uptake of 38.1 SUVMax compared with 2.8 SUVMax for the left adrenal nodule (Fig. 1). Biochemical evaluation in- cluded plasma aldosterone concentration of 1495 pmol/L (N: 80-400 pmol/L) in a seated posture and renin at 5 ng/L (N: 5-20 ng/L) to renin ratio of 299 (N <115). Following a saline suppression test, plasma aldosterone concentration remained elevated (1948 pmol/L to 1675 pmol/L) with suppressed renin levels (<5 ng/L). DHEA-S was normal (1.24 umol/L; N: 0.51-6.24 umol/L), as was androstenedione (1.2 nmol/L; N: 1.4-9.8 nmol/L) while testosterone was in the lower range of
normal (0.35 nmol/L; N: 0-2.9 nmol/L). Catecholamines, gas- trin, insulin, C-peptide levels, and pituitary panel, were nor- mal. A pituitary MRI showed a 3-mm nodule. Serum cortisol was at 80 nmol/L (N <50 nmol/L) following 1 mg overnight dexamethasone and urinary free cortisol was also slightly elevated (472 nmol/day, N: 58-306 nmol/day) but with a normal ACTH (5.6 pmol/L (N: 2-11 pmol/L)) (Table 1). The patient received one intravenous dose of dexa- methasone 6 mg during surgery as the usual anesthesia proto- col for preventing nausea, not for the risk of adrenal insufficiency. Patient underwent right “en bloc” adrenalec- tomy by laparotomy with no complications. Pathology report showed a 4-cm oncocytic ACC with marked nuclear atypia, capsular protrusion, >5 mitoses/50 HPF and atypical mitosis. Ki-67 proliferation index was at 10% and adrenal cortical ori- gin was confirmed with positive inhibin and Melan-A stain- ing. This tumor was considered malignant due to the presence of 2 major Lin-Weiss-Bisceglia criteria (>5 mi- toses/50 HPF and atypical mitosis) (19). This tumor was a low-grade ACC based on a low mitotic count and low Ki-67 proliferation index. Adjacent to the ACC was a distinct 2-cm tumor that was consistent with a benign adenoma.
Immediately postoperatively, the patient no longer needed any hypertension medication, had normal potassium levels, and aldosterone levels were <40 pmol/L. Morning cortisol was 227 nmol/L and ACTH levels were at 2 pmol/L (Table 1). The patient gave consent to be part of the ADIUVO study (NCT00777244) and was randomized to the active surveillance group without adjuvant mitotane ther- apy. Patient was followed with biochemical testing and by ad- renal imaging every 3 months during 2 years, every 6 months during 3 years, and annually afterwards.
Eight years after surgery, the patient showed no sign of radiological, clinical, or biochemical recurrence. For her pri- mary hyperparathyroidism, she underwent subtotal parathyr- oidectomy and the pathology report described parathyroid hyperplasia. Her pituitary adenoma is stable at 3 mm and nonfunctional. The patient’s left adrenal nodule is also stable in size and the most recent 1 mg dexamethasone test was nor- mal at 40 nmol/L (N < 50 nmol/L). She continues to be closely followed by her local endocrinologist (Table 1).
Methods
Germline and Somatic MEN1 Genetic Analysis
Due to a personal history of primary hyperparathyroidism and a family history of Zollinger-Ellison, the patient under- went genetic counseling for genetic analysis for the MEN1
| Laboratory results | Preop | 1 day postop | Most recent |
|---|---|---|---|
| Aldosterone (N: 80-400 pmol/L) | 1495 | <40 | 191 |
| Renin | 5 | 0.2 (N<3.4 ng/ mL/h) | 6 (N: 5-20 ng/L) |
| (N: | |||
| 5-20 ng/L) | |||
| Aldosterone to renin ratio | 299 | — | 31.8 |
| 1 mg dexamethasone suppression test | 80 | — | 40 |
| (N <50 nmol/L) | |||
| Urinary free cortisol | 472 | — | 59 |
| (nmol/day) | (N: | (N<220) | |
| 58-306) | |||
| Morning cortisol (nmol/L) | — | 227 | — |
| ACTH | 5.6 | 2 | 6.1 |
| (N: 2-11 pmol/L) | |||
| DHEAS | 1.24 | — | — |
| (N: 0.51-6.24 umol/L) | |||
| Testosterone (N: 0-2.9 nmol/L) | 0.35 | — | — |
| Androstenedione (N: 1.4-9.8 nmol/L) | 1.2 | — | — |
Abbreviations: ACTH, adrenocorticotropic hormone; DHEAS, dehydroepiandrosterone sulfate; N, normal range.
gene. Written consent was obtained from the patient for MEN1 analysis and the testing was performed in a commer- cial laboratory (Molecular Diagnosis Laboratory, Alberta Children’s Hospital, Canada). Leucocyte DNA was extracted from whole blood cells and tumoral DNA was extracted from FFPE tissues as described previously (20). Then genetic ana- lysis of leucocyte DNA and tumoral tissues were performed.
To confirm the MEN1 pathogenic variant by direct sequen- cing, exon 10 was amplified by PCR in leucocyte DNA and tu- moral ACC and APA DNA. The amplicons were directly sequenced using the Applied Biosystems 3730xl DNA Analyzer (McGill University and Genome Quebec Innovation Centre (MUGQIC), QC, Canada). The ethical committee of our institution approved the study.
Somatic Driver Mutations for PA
The patient’s adrenal tumors were also screened for driver mutations for PA. Specific exons of the coding regions were amplified by PCR in both tumoral tissues (ACC and APA) for the following genes: CTNNB1 (exon 3), KCNJ5 (exon 2), GNAS (exons 8 and 9), ATP1A1 (exons 4 and 8), ATP2B3 (exon 8), and CACNA1D (exons 6, 8, 16, 23, 27, and 33). The amplicons were directly sequenced by the same method mentioned above. All the PA driver mutation primers that were used were described previously (Supplementary Table S1) (20, 21). Another case of ACC was used as a control sample.
Immunohistochemistry
Immunohistochemical analysis was also conducted as previ- ously described (22). Original and new hematoxylin and eosin
(H&E) slides of the oncocytic ACC and adenoma were ana- lyzed by an experienced pathologist (M.L.) to confirm the presence of an oncocytic ACC and to determine the Lin- Weiss-Bisceglia score. CYP11B2, ß-catenin, and TP53 stain- ings were performed on 3-mm thick sections of deparaffinized tissue and antigens were retrieved. Slides were incubated with mouse monoclonal antibodies (Ventana BenchMark system) against ß-catenin (clone b-catenin 1, 1:200 dilution-Dako: RRID:AB_2086135), TP53 (clone Pab1801, 1:50 dilution- Leica: RRID:AB_563930) and CYP11B2 (Anti-CYP11B2, clone 41-17B, dilution 1:100-Millipore Sigma: RRID: AB_2783793). External positive controls were performed. Staining was scored semiquantitatively.
Results
Germline MEN1 Pathogenic Variant
Genetic studies revealed a pathogenic germline variant in exon 10 of the MEN1 gene (NM_130799.2 (MEN1):c.1556delC (p.Pro519fs)) confirming the diagnosis of MEN1 (Fig. 2). Loss of heterozygosity was found in tumoral DNA from both the ACC and the adenoma (Fig. 2).
Tumoral Genetic Analysis
Moreover, a pathogenic somatic variant in exon 2 of the KCNJ5 gene (NM_000890.5 (KCNJ5):c.451G>A (p.Gly151Arg)) was found only in the APA and was absent in germline DNA and in the ACC DNA. Genetic analysis of other driver PA genes did not identify any other genetic patho- genic variants (Fig. 2).
Immunohistochemical Studies
In our patient, immunohistochemical analysis showed posi- tive membranous staining and negative nucleus and cytoplas- mic staining for ß-catenin. TP53 had a wild-type aspect in the adenoma and oncocytic ACC. CYP11B2 was positive in the adenoma but was negative in the ACC, supporting that the aldosterone secretion originated from the adenoma (APA) and not from the ACC or the nontumoral parenchyma (Fig. 3A-F).
Discussion
This case illustrates a rare association of oncocytic adreno- cortical carcinoma (ACC) simultaneously with a benign aden- oma presenting with PA in a case of MEN1 disease. Identification of a somatic KCNJ5 mutation in the APA with positive aldosterone synthase staining confirmed the ad- enoma as the source of aldosterone secretion between the 2 adrenal lesions. Both MEN1 and KCNJ5 gene mutations were predicted as pathogenic. The MEN1 pathogenic variant (NM_130799.2 (MEN1):c.1556delC (p.Pro519fs)) was pre- viously described in a Belgian family where 9 members carried the variant (23). These patients presented with pituitary, parathyroid, and pancreatic manifestations of MEN1. No adrenal implication was noted; however, adrenal screen- ing was not detailed (23). The KCNJ5 pathogenic variant (NM_000890.5 (KCNJ5):c.451G>A (p.Gly151Arg)) was de- scribed as both a germline and somatic pathogenic variant leading to PA (24-26). In 2011, Choi et al studied 22 patients with APAs and discovered 2 recurrent somatic mutations (G151R and L168R) of KCNJ5 in 8/22 APAs. They also
A
Pro
Pro
Gly
Thr
Val
Ala
CC TCC TG GG AC TG TCGCT
Control DNA
MEN1 exon 10 c.1556delC, P519Lfs*40
Pro
Pro/Leu Gly/Gly Thr/Leu Val/Ser Ala/Leu
CC TCCTGGGACT GTCGCT TGGGACTGTCGCTG
Patient leucocyte DNA
B
MEN1 exon 10
c.1556delC, P519Lfs*40
Pro
Leu
Gly
Leu
Ser
Leu
CC TC TG GG AC TG TCG C TG
Adenoma FFPE DNA (LOH)
MEN1 exon 10
c.1556delC, P519Lfs*40
Pro
Leu
Gly
Leu
Ser
Leu
CC TC TG GG AC TG TCG C TG
Oncocytic ACC FFPE DNA (LOH)
C
KCNJ5 exon 2 c.451G>A, p.Gly151Arg
Ile
Gly
Tyr
Ile Gly/Arg Tyr
Ile
Gly
Tyr
ATTGGGTAT
A T TGGG TAT
A T TGGG TAT
A
Patient leucocyte DNA
Adenoma FFPE DNA
Oncocytic ACC FFPE DNA
demonstrated using in vitro studies that “channels containing KCNJ5 with G151R, T158A, or L168R mutations conduct Na+, resulting in Na+ entry, chronic depolarization, constitu- tive aldosterone production, and cell proliferation” (24). Following this discovery, the prevalence of somatic KCNJ5 mutations in several cohorts of different ethnicities were pub- lished. Patients with APAs who are of Asian ancestry tend to have higher prevalence of somatic KCNJ5 mutations in com- parison with patients of European or African descent (7, 12, 13, 27, 28). These studies led to genotype-phenotype correla- tions. In a large 2015 meta-analysis, patients harboring a som- atic KCNJ5 mutation were more likely to be female, younger, have higher aldosterone levels, and larger tumors (7). Moreover, identification of somatic KCNJ5 mutations has been shown to be a predictor of remission of hypertension fol- lowing adrenalectomy in patients with unilateral PA (29). This shows that a better understanding of the genetics under- lying PA may lead to greater genotype-phenotype correlations of patients with PA.
As mentioned above, PA is a rare occurrence in patients with MEN1. Indeed, in a study by Gatta-Cherifi et al, of the
715 patients with MEN1, 146 had adrenal involvement and 4 (2.7%) presented with PA (2). Another study by Wang et al described 121 patients with MEN1, of whom 33.9% had adrenal involvement and 2.3% presented with PA (5). Recently, a family was described in which 4 members pre- sented with concomitant MEN1 and renin-independent aldos- terone secretion (30). They were all normotensive and had a left adrenal nodule, but no genetic testing for PA driver muta- tions was performed (30). On the other hand, ACCs seem to be more common in MEN1 patients presenting with adrenal involvement, with a prevalence ranging from 4.7% to 22% (2, 5, 31). However, when considering all MEN1 patients, the overall prevalence of ACCs seems to be around 1.5% (5). The pathophysiology of ACCs in MEN1 remains to be clarified. In a study by Wang et al, the investigators present the genetic characterization of a patient with MEN1 and an ACC. The patient presented with a germline MEN1 heterozy- gous mutation (c.400_401insC), loss of heterozygosity (LOH) of the wild-type MEN1 allele in the ACC with no menin stain- ing and a heterozygous somatic CTNNB1 mutation (357del24). Moreover, TP53 staining was found in 20% of
A
D
B
E
C
F
tumoral cells. This case demonstrates that other somatic events might be responsible for the malignant transformation of adrenal lesions in MEN1 patients (5). In our case, we per- formed CTNNB1 genetic analysis, which was negative. Moreover, the somatic genetic analysis of TP53 could have been interesting, seeing that a somatic mutation in TP53 was previously described associated with MEN1 LOH in parathyroid tissue of a MEN1 patient with primary hyperthy- roidism (32). In our case, staining for TP53 and ß-Catenin were negative for the adenoma and the oncocytic ACC.
Another rare event described in our case report is the pres- ence of an adrenal collision tumors (ACT) (33). ACTs have been defined as the: “coexistence of two adjacent, but histo- logically distinct neoplasms involving the adrenal gland with- out histologic admixture at interface” (33). These tumors tend to be adjacent but within the same adrenal mass (33). A case of ACT that encompassed a pheochromocytoma and an APA has been described (34). However, we did not find any case of ACTs comprising an ACC and an APA in the literature.
In our case, immunochemistry played a crucial role in the identification of the APA. The last steps of mineralocorticoid synthesis are catalyzed by the enzyme aldosterone synthase encoded by CYP11B2 (35). Use of antibodies targeting CYP11B2 permits the discovery of aldosterone-producing sites (36). Indeed, the staining in association with the identifi- cation of the somatic KCNJ5 in the adenoma demonstrated that the aldosterone source was the adenoma and not the
carcinoma. Identification of functionality for ACCs is import- ant for follow-up. In the clinical practice guidelines on diagno- sis, treatment, and follow-up for adrenal cancer, it is recommended that after complete resection of the ACC, the patient should be monitored every 3 months with measure- ment of initially elevated steroids (37). Thus, aldosterone would not be a good follow-up marker for the adrenal cancer in this case.
Nanba et al described a 49-year-old female who presented with aldosterone and cortisol co-secretion with 2 adrenocor- tical adenomas within the same adrenal gland. After adrena- lectomy, a KCNJ5 p.T148I/T149S mutation was identified in the positive CYP11B2 staining APA and a PRKACA gene hotspot mutation (p.L206R) was identified in the negative CYP11B2 staining adenoma, revealing which adenoma was responsible for specific hormone secretion (38).
Similar to our report, in 2016, Vouillarmet et al (39) de- scribed the case of a 26-year-old male patient with severe hypertension and a hemorrhagic stroke. He was diagnosed with PA and primary bilateral macronodular adrenal hyper- plasia, with an aldosterone secretion that lateralized to the right adrenal. He underwent right adrenalectomy. Pathology and genetic reports showed that one nodule harbored a KCNJ5 somatic mutation and had a positive aldosterone syn- thase staining. The patient was later diagnosed with familial adenomatous polyposis due to the discovery of colic polyps and dysplasia and the identification of a heterozygous
germline mutation in APC. Moreover, LOH of APC was iden- tified in the APA (39). Both this case and our case support the two-hit theory for development of adrenal tumors. In our case, the patient presented with a first hit (germline MEN1 pathogenic variant) and a second hit (LOH of MEN1 in both adrenal tumors). It is believed that these hits lead to cor- tical cell proliferation, whereas the KCNJ5 pathogenic variant drives hormonal secretion (39).
In summary, this case describes the rare event of an ACT en- compassing an APA and an ACC in a patient with MEN1 syn- drome carrying a germline pathogenic MENI variant. Use of genetic testing and immunochemistry helped identify the source of aldosterone secretion originating from the APA and not the ACC, which is an important finding for follow-up. Moreover, genetic analyses provided better understanding of the pathogenesis of adrenal tumorigenesis in MEN1 patients with identification of LOH in both tumors. This case provides new insights on adrenal tumor development in MEN1 pa- tients and in primary aldosteronism.
Funding
This study was supported by FRQS (Fonds de recherche du Québec-Santé) (IB) and Formation de recherche pour les résidents-Résidence complémentaire en recherche: phase 1 FRQS (SPL).
Disclosures/Conflict of Interest
The authors have nothing to disclose.
Data Availability
Original data generated and analyzed during this study are in- cluded in this published article or in the data repositories listed in References.
References
1. Thakker RV, Newey PJ, Walls GV, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012;97(9):2990-3011.
2. Gatta-Cherifi B, Chabre O, Murat A, et al. Adrenal involvement in MEN1. Analysis of 715 cases from the Groupe d’etude des Tumeurs Endocrines database. Eur J Endocrinol. 2012;166(2): 269-279.
3. Funder JW, Carey RM, Mantero F, et al. The management of pri- mary aldosteronism: case detection, diagnosis, and treatment: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(5):1889-1916.
4. Vaidya A, Mulatero P, Baudrand R, Adler GK. The expanding spec- trum of primary aldosteronism: implications for diagnosis, patho- genesis, and treatment. Endocr Rev. 2018;39(6):1057-1088.
5. Wang W, Han R, Ye L, et al. Adrenocortical carcinoma in patients with MEN1: a kindred report and review of the literature. Endocr Connect. 2019;8(3):230-238.
6. Mulatero P, Monticone S, Deinum J, et al. Genetics, prevalence, screening and confirmation of primary aldosteronism: a position statement and consensus of the Working Group on Endocrine Hypertension of The European Society of Hypertension. J Hypertens. 2020;38(10):1919-1928.
7. Lenzini L, Rossitto G, Maiolino G, Letizia C, Funder JW, Rossi GP. A meta-analysis of somatic KCNJ5 K(+) channel mutations in 1636 patients with an aldosterone-producing adenoma. J Clin Endocrinol Metab. 2015;100(8):E1089-E1095.
8. Scholl UI, Healy JM, Thiel A, et al. Novel somatic mutations in pri- mary hyperaldosteronism are related to the clinical, radiological and pathological phenotype. Clin Endocrinol (Oxf). 2015;83(6): 779-777.
9. Åkerström T, Crona J, Delgado Verdugo A, et al. Comprehensive re-sequencing of adrenal aldosterone producing lesions reveal three somatic mutations near the KCNJ5 potassium channel selectivity filter. PLoS One. 2012;7(7):e41926.
10. Boulkroun S, Beuschlein F, Rossi G, et al. Prevalence, clinical, and molecular correlates of KCNJ5 mutations in primary aldosteron- ism. Hypertension. 2012;59(3):592-559.
11. Zheng F-F, Zhu L-M, Nie A-F, et al. Clinical characteristics of som- atic mutations in Chinese patients with aldosterone-producing ad- enoma. Hypertension. 2015;65(3):622-662.
12. Wang B, Li X, Zhang X, et al. Prevalence and characterization of somatic mutations in Chinese aldosterone-producing adenoma pa- tients. Medicine (Baltimore). 2015;94(16):e708.
13. Warachit W, Atikankul T, Houngngam N, Sunthornyothin S. Prevalence of somatic KCNJ5 mutations in Thai patients with aldosterone-producing adrenal adenomas. J Endocr Soc. 2018; 2(10):1137-1111.
14. Scholl UI, Goh G, Stölting G, et al. Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism. Nat Genet. 2013;45(9): 1050-1054.
15. Azizan EAB, Poulsen H, Tuluc P, et al. Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension. Nat Genet. 2013;45(9):1055-1060.
16. Beuschlein F, Boulkroun S, Osswald A, et al. Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension. Nat Genet. 2013;45(4):440-4, 444e1-2.
17. Nanba K, Blinder AR, Rege J, et al. Somatic CACNA1H mutation as a cause of aldosterone-producing adenoma. Hypertension. 2020;75(3):645-649.
18. Dutta RK, Arnesen T, Heie A, et al. A somatic mutation in CLCN2 identified in a sporadic aldosterone-producing adenoma. Eur J Endocrinol. 2019;181(5):K37-K41.
19. Wong DD, Spagnolo DV, Bisceglia M, Havlat M, McCallum D, Platten MA. Oncocytic adrenocortical neoplasms-a clinicopatho- logic study of 13 new cases emphasizing the importance of their rec- ognition. Hum Pathol. 2011;42(4):489-499.
20. Gagnon N, Cáceres-Gorriti KY, Corbeil G, et al. Genetic character- ization of GnRH/LH-responsive primary aldosteronism. J Clin Endocrinol Metab. 2018;103(8):2926-2935.
21. Parisien-La Salle S, Gilles C, Zaki EH, et al. 2022. Supplemental ma- terials: genetic dissection of primary aldosteronism in a patient with MEN1 and ipsilateral adrenocortical carcinoma and adenoma. doi:10.5281/zenodo.7199210. Date of deposit 14 October 2022.
22. El Ghorayeb N, Rondeau G, Latour M, et al. Rapid and complete remission of metastatic adrenocortical carcinoma persisting 10 years after treatment with mitotane monotherapy: case report and review of the literature. Medicine (Baltimore). 2016;95(13):e3180.
23. Poncin J, Abs R, Velkeniers B, et al. Mutation analysis of the MEN1 gene in Belgian patients with multiple endocrine neoplasia type 1 and related diseases. Hum Mutat. 1999;13(1):54-60.
24. Choi M, Scholl UI, Yue P, et al. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science. 2011;331(6018):768-772.
25. Scholl UI, Nelson-Williams C, Yue P, et al. Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5. Proc Natl Acad Sci U S A. 2012;109(7):2533-2538.
26. Mulatero P, Tauber P, Zennaro M-C, et al. KCNJ5 mutations in European families with nonglucocorticoid remediable familial hy- peraldosteronism. Hypertension. 2012;59(2):235-240.
27. Nanba K, Omata K, Else T, et al. Targeted molecular characteriza- tion of aldosterone-producing adenomas in White Americans. J Clin Endocrinol Metab. 2018;103(10):3869-3876.
28. Nanba K, Omata K, Gomez-Sanchez CE, et al. Genetic characteris- tics of aldosterone-producing adenomas in blacks. Hypertension. 2019;73(4):885-892.
29. Vilela LAP, Rassi-Cruz M, Guimaraes AG, et al. KCNJ5 somatic mutation is a predictor of hypertension remission after adrenalec- tomy for unilateral primary aldosteronism. J Clin Endocrinol Metab. 2019;104(10):4695-4702.
30. Obata Y, Takayama K, Maruo Y, et al. Coexistence of renin-independent aldosterone secretion and multiple endocrine neoplasia type 1 within a family. J Endocr Soc. 2022;6(3):bvac009.
31. Langer P, Cupisti K, Bartsch DK, et al. Adrenal involvement in mul- tiple endocrine neoplasia type 1. World J Surg. 2002;26(8): 891-896.
32. Romero Arenas MA, Fowler RG, San Lucas FA, et al. Preliminary whole-exome sequencing reveals mutations that imply common tumorigenicity pathways in multiple endocrine neoplasia type 1 pa- tients. Surgery. 2014;156(6):1351-1357; discussion 1357-8.
33. Katabathina VS, Flaherty E, Kaza R, Ojili V, Chintapalli KN, Prasad SR. Adrenal collision tumors and their mimics: multimodal- ity imaging findings. Cancer Imaging. 2013;13(4):602-610.
34. Sakamoto N, Tojo K, Saito T, et al. Coexistence of aldosterone- producing adrenocortical adenoma and pheochromocytoma in an ipsilateral adrenal gland. Endocr J. 2009;56(2):213-219.
35. Monticone S, Castellano I, Versace K, et al. Immunohistochemical, genetic and clinical characterization of sporadic aldosterone- producing adenomas. Mol Cell Endocrinol. 2015;411:146-154.
36. Volpe C, Hamberger B, Zedenius J, Juhlin CC. Impact of immuno- histochemistry on the diagnosis and management of primary aldos- teronism: an important tool for improved patient follow-up. Scand J Surg. 2020;109(2):133-142.
37. Berruti A, Baudin E, Gelderblom H, et al. Adrenal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23(Suppl 7):vii131-vii138.
38. Nanba K, Omata K, Tomlins SA, et al. Double adrenocortical aden- omas harboring independent KCNJ5 and PRKACA somatic muta- tions. Eur J Endocrinol. 2016;175(2):K1-K6.
39. Vouillarmet J, Fernandes-Rosa F, Graeppi-Dulac J, et al. Aldosterone-producing adenoma with a somatic KCNJ5 mutation revealing APC-dependent familial adenomatous polyposis. J Clin Endocrinol Metab. 2016;101(11):3874-3878.