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Article ; Online: An Overview of the Heterogeneous Causes of Cushing Syndrome Resulting From Primary Macronodular Adrenal Hyperplasia (PMAH).

Charchar, Helaine Laiz Silva / Fragoso, Maria Candida Barisson Villares

Journal of the Endocrine Society

2022 Volume 6, Issue 5, Page(s) bvac041

Abstract: Primary macronodular adrenal hyperplasia (PMAH) is considered a rare cause of adrenal Cushing syndrome, is pituitary ACTH-independent, generally results from bilateral adrenal macronodules (>1 cm), and is often associated with variable cortisol secretion, ...

Abstract	Primary macronodular adrenal hyperplasia (PMAH) is considered a rare cause of adrenal Cushing syndrome, is pituitary ACTH-independent, generally results from bilateral adrenal macronodules (>1 cm), and is often associated with variable cortisol secretion, resulting in a heterogeneous clinical presentation. Recent advances in the molecular pathogenesis of PMAH have offered new insights into the comprehension of this heterogeneous and complex adrenal disorder. Different molecular mechanisms involving the actors of the cAMP/protein kinase A pathway have been implicated in the development of PMAH, including germline and/or somatic molecular defects such as hyperexpression of the G-protein aberrant receptors and pathogenic variants of
Language	English
Publishing date	2022-03-17
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2472-1972
ISSN (online)	2472-1972
DOI	10.1210/jendso/bvac041
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Article ; Online: ARMC5 controls the degradation of most Pol II subunits, and ARMC5 mutation increases neural tube defect risks in mice and humans.

Luo, Hongyu / Lao, Linjiang / Au, Kit Sing / Northrup, Hope / He, Xiao / Forget, Diane / Gauthier, Marie-Soleil / Coulombe, Benoit / Bourdeau, Isabelle / Shi, Wei / Gagliardi, Lucia / Fragoso, Maria Candida Barisson Villares / Peng, Junzheng / Wu, Jiangping

Genome biology

2024 Volume 25, Issue 1, Page(s) 19

Abstract: Background: Neural tube defects (NTDs) are caused by genetic and environmental factors. ARMC5 is part of a novel ubiquitin ligase specific for POLR2A, the largest subunit of RNA polymerase II (Pol II).: Results: We find that ARMC5 knockout mice have ... ...

Abstract	Background: Neural tube defects (NTDs) are caused by genetic and environmental factors. ARMC5 is part of a novel ubiquitin ligase specific for POLR2A, the largest subunit of RNA polymerase II (Pol II). Results: We find that ARMC5 knockout mice have increased incidence of NTDs, such as spina bifida and exencephaly. Surprisingly, the absence of ARMC5 causes the accumulation of not only POLR2A but also most of the other 11 Pol II subunits, indicating that the degradation of the whole Pol II complex is compromised. The enlarged Pol II pool does not lead to generalized Pol II stalling or a generalized decrease in mRNA transcription. In neural progenitor cells, ARMC5 knockout only dysregulates 106 genes, some of which are known to be involved in neural tube development. FOLH1, critical in folate uptake and hence neural tube development, is downregulated in the knockout intestine. We also identify nine deleterious mutations in the ARMC5 gene in 511 patients with myelomeningocele, a severe form of spina bifida. These mutations impair the interaction between ARMC5 and Pol II and reduce Pol II ubiquitination. Conclusions: Mutations in ARMC5 increase the risk of NTDs in mice and humans. ARMC5 is part of an E3 controlling the degradation of all 12 subunits of Pol II under physiological conditions. The Pol II pool size might have effects on NTD pathogenesis, and some of the effects might be via the downregulation of FOLH1. Additional mechanistic work is needed to establish the causal effect of the findings on NTD pathogenesis.
MeSH term(s)	Animals ; Humans ; Mice ; Armadillo Domain Proteins/genetics ; Folic Acid/metabolism ; Mice, Knockout ; Mutation ; Neural Tube Defects/genetics ; Neural Tube Defects/epidemiology ; Spinal Dysraphism/genetics
Chemical Substances	Armadillo Domain Proteins ; ARMC5 protein, human ; Folic Acid (935E97BOY8) ; Armc5 protein, mouse
Language	English
Publishing date	2024-01-15
Publishing country	England
Document type	Journal Article
ZDB-ID	2040529-7
ISSN	1474-760X ; 1474-760X
ISSN (online)	1474-760X
ISSN	1474-760X
DOI	10.1186/s13059-023-03147-w
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Article ; Online: Neuroradiological features of patients with bilateral macronodular adrenocortical disease and meningiomas associated or not with genetic variants of ARMC5- a case series.

Salame, Arthur Araújo Massoud / Charchar, Helaine Laiz Silva / de Oliveira Dourado, José Paulo / Mendonca, Berenice / Alencar, Guilherme Asmar / de Araújo, Leonardo José Tadeu / Arantes, Paula Ricci / Rabelo, Nicollas Nunes / Figueiredo, Eberval Gadelha / Fragoso, Maria Candida Barisson Villares

Journal of neuro-oncology

2024

Abstract: Introduction: Meningiomas are the most common primary brain and central nervous system tumors, accounting for approximately 40% of these tumors. The most important exams for the radiological study of meningiomas are computed tomography (CT) and magnetic ...

Abstract	Introduction: Meningiomas are the most common primary brain and central nervous system tumors, accounting for approximately 40% of these tumors. The most important exams for the radiological study of meningiomas are computed tomography (CT) and magnetic resonance imaging (MRI). We aimed to analyze the radiological features of patients with meningioma related to the simultaneous presence of bilateral macronodular adrenocortical disease (BMAD), with or without pathogenic variants of ARMC5. Methods: This study included 10 patients who were diagnosed with BMAD. All of them had a radiological diagnosis of expansive brain lesions suggestive of meningioma. All patients underwent brain MRI and a neuroradiolgist analyzed the following parameters: number, site and size of lesions; presence of calcification, edema and bone involvement. Results and discussion: Eight patients presented with germline variants of ARMC5; the other 2, did not. The most significant result was the incidence of multiple meningiomas, which was 50% in BMAD patients, whereas the average incidence described thus far is lower than 10%. Considering location, the 22 tumors in the BMAD patients were 5 convexity tumors (22.7%), and 17 skull base tumors (77.2%), the opposite proportion of patients without BMAD. A total of 40.9% of the tumors had calcification, 9% had cerebral edema and 40.9% had bone invasion due to hyperostosis. The literature describes meningioma calcification in 25% of patients, bone invasion by tumor hyperostosis in 20%, and cerebral edema in approximately 60%. Conclusion: Relevant results were found considering the rate of multiple meningiomas and tumor location. This finding reinforces the need for further research into the neurological effects caused by genetic variants of ARMC5 in patients with BMAD.
Language	English
Publishing date	2024-04-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	604875-4
ISSN	1573-7373 ; 0167-594X
ISSN (online)	1573-7373
ISSN	0167-594X
DOI	10.1007/s11060-024-04680-9
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Article ; Online: Resolution of Cyclicity After Pasireotide LAR in a Patient With Cushing Disease.

Machado, Márcio Carlos / Cescato, Valter Angelo Sperling / Fragoso, Maria Candida Barisson Villares / Bronstein, Marcello Delano

AACE clinical case reports

2021 Volume 7, Issue 4, Page(s) 277–281

Abstract: Objective: The cyclicity (CIC) of cortisol spontaneously occurs in a minority of patients with Cushing syndrome (CS). When it arises, diagnostic and therapeutic approaches become more challenging. This study aimed to report a patient with Cushing ... ...

Abstract	Objective: The cyclicity (CIC) of cortisol spontaneously occurs in a minority of patients with Cushing syndrome (CS). When it arises, diagnostic and therapeutic approaches become more challenging. This study aimed to report a patient with Cushing disease (CD) who achieved normalization of cortisol and CIC pattern with pasireotide long-acting release (pasi/LAR). Methods: A 43-year-old female patient related an 8-month history of CS. An 8-mm pituitary nodule depicted by magnetic resonance imaging, serum cortisol suppression of >50% after 8 mg of dexamethasone therapy, and the absence of other lesions were compatible with a CD diagnosis. The patient presented with a CIC pattern with 1 episode before and 17 episodes after an unsuccessful pituitary surgery. Results: Medical treatment with cabergoline alone up to 3.5 mg/wk and a combined treatment with ketoconazole 400 mg/d did not improve CIC CS. Pasi/LAR was initiated at a dose of 20 mg/mo. A few days after the first dose, the patient experienced symptoms suggestive of adrenal insufficiency. The medication and dose were maintained for 24 months. During this period, there was a normalization of UFC levels and progressive clinical improvement. Additionally, new episodes of CIC were not observed. Conclusion: A CD patient with a challenging issue of CIC was reported. The condition was not controlled after pituitary surgery and by the combined treatment with cabergoline and ketoconazole, although hypercortisolism was abated by the continuous use of pasi/LAR. To our knowledge, this is the first report as regards the use of this medication to control CIC in a patient with CD.
Language	English
Publishing date	2021-03-09
Publishing country	United States
Document type	Case Reports
ISSN	2376-0605
ISSN (online)	2376-0605
DOI	10.1016/j.aace.2021.02.007
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Article ; Online: Pregnancy after pituitary surgery does not influence the recurrence of Cushing's disease.

Lousada, Lia Mesquita / Tapia, Mariuxi Jacqueline Borja / Cescato, Valter Angelo Sperling / da Silva, Gilberto Ochman / Musolino, Nina Rosa Castro / Fragoso, Maria Candida Barisson Villares / Bronstein, Marcello Delano / Machado, Marcio Carlos

Endocrine

2022 Volume 78, Issue 3, Page(s) 552–558

Abstract: Purpose: Pregnancy is associated with the activation of the hypothalamus-pituitary-adrenal axis, which can cause a misdiagnosis of Cushing's syndrome. The aim of this study is to evaluate the impact of pregnancy after pituitary surgery on the recurrence ...

Abstract	Purpose: Pregnancy is associated with the activation of the hypothalamus-pituitary-adrenal axis, which can cause a misdiagnosis of Cushing's syndrome. The aim of this study is to evaluate the impact of pregnancy after pituitary surgery on the recurrence rate in Cushing's disease (CD) patients. Methods: This was a retrospective study in a tertiary center. Between 1990 and 2020, 355 CD patients underwent pituitary surgery. Of those, we included 113 female patients who were ≤ 45 years old (median age of 32 years, 14-45), PS remission, a follow-up of ≥6 months (median of 122 months, 6-402) and an available obstetric history. Recurrence was defined as the diagnosis of Cushing's syndrome via at least two altered first-line methods. The patients were divided into two subgroups according to pregnancy: no pregnancy or pregnancy prior to CD diagnosis (NP/PP) and pregnancy after CD pituitary surgery (PA). Results: Overall, recurrence occurred in 43 out of 113 patients (38%). A higher recurrence rate was seen in the PA subgroup (11/22, 50%), but there was no significant difference between the NP/PP subgroup (32/91, 35%). No difference in survival-free recurrence (SFR) was found between NP/PP and PA subgroups. The lower SFR was related to a higher PS plasma ACTH and normal pituitary at pathological analyses. Conclusions: There was no difference in the recurrence rate in patients according to pregnancy history. Other studies with higher numbers of patients are needed to confirm these data.
MeSH term(s)	Humans ; Female ; Adult ; Middle Aged ; Pituitary ACTH Hypersecretion/surgery ; Pituitary ACTH Hypersecretion/complications ; Cushing Syndrome/diagnosis ; Cushing Syndrome/surgery ; Pituitary Neoplasms/surgery ; Retrospective Studies ; Pituitary Gland/surgery ; Recurrence ; Hydrocortisone
Chemical Substances	Hydrocortisone (WI4X0X7BPJ)
Language	English
Publishing date	2022-08-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	1194484-5
ISSN	1559-0100 ; 1355-008X ; 0969-711X
ISSN (online)	1559-0100
ISSN	1355-008X ; 0969-711X
DOI	10.1007/s12020-022-03151-3
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Zs.A 3884: Show issues

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Article ; Online: Crossed-Probes Cryoablation for the Treatment of a Sclerotic Vertebral Metastasis Abutting the Spinal Canal.

de Freitas, Ricardo Miguel Costa / Caldas, José Guilherme Mendes Pereira / Verst, Silvia Mazzali / Hoff, Ana Oliveira / Bezerra Neto, João Evangelista / Fragoso, Maria Candida Barisson Villares

Journal of vascular and interventional radiology : JVIR

2020 Volume 31, Issue 2, Page(s) 284–285

MeSH term(s)	Adrenal Cortex Neoplasms/diagnostic imaging ; Adrenal Cortex Neoplasms/pathology ; Adrenocortical Carcinoma/diagnostic imaging ; Adrenocortical Carcinoma/secondary ; Adrenocortical Carcinoma/surgery ; Adult ; Cryosurgery ; Female ; Humans ; Lumbar Vertebrae/diagnostic imaging ; Lumbar Vertebrae/pathology ; Lumbar Vertebrae/surgery ; Metastasectomy/methods ; Radiography, Interventional ; Sclerosis ; Spinal Neoplasms/diagnostic imaging ; Spinal Neoplasms/secondary ; Spinal Neoplasms/surgery ; Treatment Outcome
Language	English
Publishing date	2020-01-30
Publishing country	United States
Document type	Case Reports
ZDB-ID	1137756-2
ISSN	1535-7732 ; 1051-0443
ISSN (online)	1535-7732
ISSN	1051-0443
DOI	10.1016/j.jvir.2019.11.006
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Zs.A 3720: Show issues

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Article ; Online: Role of the Mevalonate Pathway in Adrenocortical Tumorigenesis.

Lima-Valassi, Helena Panteliou / Lerario, Antonio Marcondes / Montenegro, Luciana Ribeiro / Fragoso, Maria Candida Barisson Villares / Almeida, Madson Queiroz / Mendonca, Berenice Bilharinho / Lin, Chin Jia

Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme

2020 Volume 53, Issue 2, Page(s) 124–131

Abstract: 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is the rate-limiting enzyme of the mevalonate pathway, which generates cholesterol and non-sterol compounds such as isoprenoid, which are involved in key steps of tumorigenesis such as cell growth ... ...

Abstract	3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is the rate-limiting enzyme of the mevalonate pathway, which generates cholesterol and non-sterol compounds such as isoprenoid, which are involved in key steps of tumorigenesis such as cell growth and proliferation. Our aim was to evaluate the role of the mevalonate pathway in adrenocortical tumors (ACTs). Expression pattern of
MeSH term(s)	Adolescent ; Adrenal Cortex Neoplasms/genetics ; Adrenal Cortex Neoplasms/metabolism ; Adrenal Cortex Neoplasms/pathology ; Adult ; Aged ; Carcinogenesis/metabolism ; Carcinogenesis/pathology ; Cell Line, Tumor ; Cell Survival/genetics ; Child, Preschool ; Cholesterol/metabolism ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Infant ; Male ; Metabolic Networks and Pathways/genetics ; Mevalonic Acid/metabolism ; Middle Aged ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Protein Prenylation/genetics ; Steroids/biosynthesis ; Young Adult
Chemical Substances	Neoplasm Proteins ; Steroids ; Cholesterol (97C5T2UQ7J) ; Mevalonic Acid (S5UOB36OCZ)
Language	English
Publishing date	2020-12-11
Publishing country	Germany
Document type	Journal Article
ZDB-ID	80125-2
ISSN	1439-4286 ; 0018-5043
ISSN (online)	1439-4286
ISSN	0018-5043
DOI	10.1055/a-1322-2943
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Article ; Online: Adrenal cysts of lymphatic origin: A clinical and pathological study of six cases and systematic literature review.

Marques-Piubelli, Mario L / Gonzales, Eloiza Wilma Poma / Gonçalves, Victor Lucas / Balancin, Marcelo Luiz / Botelho, Maria Luiza A A / Yamauchi, Fernando Ide / de Mello Ando, Sabrina / Brondani, Vania Balderrama / Chambo, Jose Luis / Fragoso, Maria Candida Barisson Villares / Zerbini, Maria Claudia Nogueira

Annals of diagnostic pathology

2022 Volume 57, Page(s) 151888

Abstract: Adrenal cysts are rare, benign, and usually asymptomatic, being detected as an incidental finding on imaging methods. Adrenal Cysts of Lymphatic Origin (ACLO) and Adrenal Lymphangiomas (AL) are types of endothelial cyst and are the most prevalent subtype ...

Abstract	Adrenal cysts are rare, benign, and usually asymptomatic, being detected as an incidental finding on imaging methods. Adrenal Cysts of Lymphatic Origin (ACLO) and Adrenal Lymphangiomas (AL) are types of endothelial cyst and are the most prevalent subtype in this series. This study aims to present a single institutional experience of these rare cysts and compare their features with those found in the review of existing literature on ACLO and AL. Overall, thirteen cases of adrenal cysts were diagnosed and surgically excised during the study period, onto which we performed immunohistochemistry using a panel of antibodies (CD31, CD34, Pan Cytokeratin AE-1/AE-3, Factor VII, D2-40, and ERG). Four cases of ACLO and two AL were found. The lesions predominantly affected right adrenal, and the majority of patients were middle-age females, of Caucasian ethnicity, and asymptomatic. In our literature review, we found 108 cases of ACLO/AL from 57 articles with similar sex and age distribution. The diagnosis and subclassification of adrenal cysts are challenging, and there is a significant overlapping between the definition of ACLO and AL.
MeSH term(s)	Adrenal Gland Neoplasms/diagnosis ; Adrenal Gland Neoplasms/pathology ; Cysts/pathology ; Female ; Humans ; Immunohistochemistry ; Middle Aged
Language	English
Publishing date	2022-01-04
Publishing country	United States
Document type	Journal Article ; Systematic Review
ZDB-ID	1440011-x
ISSN	1532-8198 ; 1092-9134
ISSN (online)	1532-8198
ISSN	1092-9134
DOI	10.1016/j.anndiagpath.2021.151888
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Zs.A 5463: Show issues

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Article ; Online: ARMC5 mutations are associated with high levels of proliferating cell nuclear antigen and the presence of the serotonin receptor 5HT4R in PMAH nodules.

Conceição, Barbara Brito da / Cavalcante, Isadora Pontes / Kremer, Jean Lucas / Auricino, Thais Barabba / Bento, Eduarda Corrêa / Zerbini, Maria Claudia Nogueira / Fragoso, Maria Candida Barisson Villares / Lotfi, Claudimara Ferini Pacicco

Archives of endocrinology and metabolism

2020 Volume 64, Issue 4, Page(s) 390–401

Abstract: Objective To analyze the morphological and functional characteristics of primary macronodular adrenal hyperplasia (PMAH) nodules carrying or not carrying ARMC5 mutations and the consequences of the presence of mutations in terms of the pattern of ... ...

Abstract	Objective To analyze the morphological and functional characteristics of primary macronodular adrenal hyperplasia (PMAH) nodules carrying or not carrying ARMC5 mutations and the consequences of the presence of mutations in terms of the pattern of macronodule composition and functional state. Subjects and methods The analyses were performed by hematoxylin-eosin staining, immunohistochemistry, microdissection of spongiocyte tissue and RT-qPCR of histological sections from 16 patients diagnosed with PMAH with germline (5) or germline/somatic mutations (5) and without mutations (6) in the ARMC5 gene. Results Hyperplastic nodules were predominantly composed of spongiocytes in mutated and nonmutated sections. ARMC5 mRNA expression in spongiocytes was higher in ARMC5-mutated nodules than in ARMC5-nonmutated nodules, and homogenous ARMC5 protein distribution was observed. The presence of arginine-vasopressin receptor (AVP1AR) and ectopic ACTH production were observed in both cell populations regardless of ARMC5 mutations; the numbers of serotonin receptor (5HT4R)- and proliferating cell nuclear antigen (PCNA)-positive cells were higher in macronodules carrying ARMC5 mutations than in those without mutations. Conclusions Our results suggest that the presence of ARMC5 mutations does not interfere with the pattern of distribution of spongiocytes and compact cells or with the presence of AVP1AR, gastric-inhibitory polypeptide receptor (GIPR) and ectopic ACTH. Nevertheless, the higher numbers of PCNA-positive cells in mutated nodules than in nonmutated nodules suggest that mutated ARMC5 can be related to higher proliferation rates in these cells. In conclusion, our results provide more information about the crosstalk among abnormal GPCRs, ectopic ACTH in steroidogenesis and the ARMC5 gene, which may be relevant in understanding the pathogenesis and diagnosis of patients with PMAH.
MeSH term(s)	Armadillo Domain Proteins/genetics ; Humans ; Mutation ; Proliferating Cell Nuclear Antigen ; Receptors, Serotonin, 5-HT4 ; Serotonin
Chemical Substances	ARMC5 protein, human ; Armadillo Domain Proteins ; Proliferating Cell Nuclear Antigen ; Receptors, Serotonin, 5-HT4 (158165-40-3) ; Serotonin (333DO1RDJY)
Language	English
Publishing date	2020-04-06
Publishing country	Brazil
Document type	Journal Article
ISSN	2359-4292
ISSN (online)	2359-4292
DOI	10.20945/2359-3997000000236
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Article ; Online: Cullin 3 targets the tumor suppressor gene ARMC5 for ubiquitination and degradation.

Cavalcante, Isadora Pontes / Vaczlavik, Anna / Drougat, Ludivine / Lotfi, Claudimara Ferini Pacicco / Perlemoine, Karine / Ribes, Christopher / Rizk-Rabin, Marthe / Clauser, Eric / Fragoso, Maria Candida Barisson Villares / Bertherat, Jérôme / Ragazzon, Bruno

Endocrine-related cancer

2020 Volume 27, Issue 4, Page(s) 221–230

Abstract: ARMC5 (Armadillo repeat containing 5 gene) was identified as a new tumor suppressor gene responsible for hereditary adrenocortical tumors and meningiomas. ARMC5 is ubiquitously expressed and encodes a protein which contains a N-terminal Armadillo repeat ... ...

Abstract	ARMC5 (Armadillo repeat containing 5 gene) was identified as a new tumor suppressor gene responsible for hereditary adrenocortical tumors and meningiomas. ARMC5 is ubiquitously expressed and encodes a protein which contains a N-terminal Armadillo repeat domain and a C-terminal BTB (Bric-a-Brac, Tramtrack and Broad-complex) domain, both docking platforms for numerous proteins. At present, expression regulation and mechanisms of action of ARMC5 are almost unknown. In this study, we showed that ARMC5 interacts with CUL3 requiring its BTB domain. This interaction leads to ARMC5 ubiquitination and further degradation by the proteasome. ARMC5 alters cell cycle (G1/S phases and cyclin E accumulation) and this effect is blocked by CUL3. Moreover, missense mutants in the BTB domain of ARMC5, identified in patients with multiple adrenocortical tumors, are neither able to interact and be degraded by CUL3/proteasome nor alter cell cycle. These data show a new mechanism of regulation of the ARMC5 protein and open new perspectives in the understanding of its tumor suppressor activity.
MeSH term(s)	Armadillo Domain Proteins/metabolism ; Cullin Proteins/metabolism ; Humans ; Transfection ; Ubiquitination
Chemical Substances	ARMC5 protein, human ; Armadillo Domain Proteins ; Cullin Proteins
Language	English
Publishing date	2020-02-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1218450-0
ISSN	1479-6821 ; 1351-0088
ISSN (online)	1479-6821
ISSN	1351-0088
DOI	10.1530/ERC-19-0502
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