Referral Center for Rare Adrenal Diseases

Paris, France

Referral Center for Rare Adrenal Diseases

Paris, France
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Gaujoux S.,University of Paris Descartes | Aime A.,Referral Center for Rare Adrenal Diseases | Assie G.,University of Paris Descartes | Ciuni R.,Referral Center for Rare Adrenal Diseases | And 3 more authors.
ANZ Journal of Surgery | Year: 2017

Background: Adrenal incidentalomas are increasingly diagnosed and include a wide spectrum of lesions from benign adenomas to secreting or malignant lesions. The aim of the present study is to report a large single-institution experience of patients undergoing surgery for adrenal incidentaloma with particular attention to their diagnosis and post-operative course and the evolution of surgical practice over time. Methods: From 1993 to 2013, 274 patients underwent adrenalectomy for incidentaloma. All patients underwent standardized clinical, hormonal and imaging assessments. Results: Patients were mainly female (63.1%; n=173), and the median age of patients was 56.5years. After a complete hormonal evaluation, 47.9% (n=129) of incidentalomas were classified as secreting tumours, including 24.4% (n=67) subclinical cortisol-secreting adenomas and 18.9% (n=52) pheochromocytomas. Adrenocortical carcinomas represented 9.5% (n=26) of incidentalomas, and the risk of malignancy was significantly correlated with tumour size. The conversion rate after laparoscopic adrenalectomy (90.9%; n=249) was 3.2% (n=8). The overall morbidity rate was 13.9%, which included a 4.4% rate of severe morbidity (Clavien-Dindo≥3). From 2008 onwards, there was a significant decrease (P<0.001) in the use of surgical approaches for non-secreting adenomas. Conclusion: After a complete work-up, half of the incidentalomas were classified as subclinical oversecreting adrenal lesions and 10% proved to be malignant adrenocortical carcinomas. The debatable use of surgical approaches for benign nonfunctioning adenomas significantly decreased over time. © 2017 Royal Australasian College of Surgeons.

Assie G.,University of Paris Descartes | Assie G.,Referral Center for Rare Adrenal Diseases | Libe R.,Referral Center for Rare Adrenal Diseases | Espiard S.,University of Paris Descartes | And 19 more authors.
New England Journal of Medicine | Year: 2013

BACKGROUND: Corticotropin-independent macronodular adrenal hyperplasia may be an incidental finding or it may be identified during evaluation for Cushing's syndrome. Reports of familial cases and the involvement of both adrenal glands suggest a genetic origin of this condition. METHODS: We genotyped blood and tumor DNA obtained from 33 patients with corticotropin-independent macronodular adrenal hyperplasia (12 men and 21 women who were 30 to 73 years of age), using single-nucleotide polymorphism arrays, microsatellite markers, and whole-genome and Sanger sequencing. The effects of armadillo repeat containing 5 (ARMC5) inactivation and overexpression were tested in cell-culture models. RESULTS: The most frequent somatic chromosome alteration was loss of heterozygosity at 16p (in 8 of 33 patients for whom data were available [24%]). The most frequent mutation identified by means of whole-genome sequencing was in ARMC5, located at 16p11.2. ARMC5 mutations were detected in tumors obtained from 18 of 33 patients (55%). In all cases, both alleles of ARMC5 carried mutations: one germline and the other somatic. In 4 patients with a germline ARMC5 mutation, different nodules from the affected adrenals harbored different secondary ARMC5 alterations. Transcriptome-based classification of corticotropin-independent macronodular adrenal hyperplasia indicated that ARMC5 mutations influenced gene expression, since all cases with mutations clustered together. ARMC5 inactivation decreased steroidogenesis in vitro, and its overexpression altered cell survival. CONCLUSIONS: Some cases of corticotropin-independent macronodular adrenal hyperplasia appear to be genetic, most often with inactivating mutations of ARMC5, a putative tumor-suppressor gene. Genetic testing for this condition, which often has a long and insidious prediagnostic course, might result in earlier identification and better management. (Funded by Agence Nationale de la Recherche and others.) Copyright © 2013 Massachusetts Medical Society.

Bricaire L.,Referral Center for Rare Adrenal Diseases | Van Haecke C.,Hopital Cochin | Laurent-Roussel S.,Assistance Publique Hopitaux de Paris | Jrad G.,Referral Center for Rare Adrenal Diseases | And 9 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2015

Context: The incidence of syphilis has been increasing in recent decades in Western countries. Pituitary involvement is very unusual in syphilis. This infectious disease is not often considered in the workup of a patient with hypophysitis. Case: We report the case of a 28-year-old man who was admitted for headaches worsening over 1 month that became resistant to paracetamol. A magnetic resonance imaging scan revealed a heterogeneous pituitary mass suggesting a pituitary tumor. Hormonal investigations showed partial corticotropic and thyrotropic deficiencies. Headaches required high doses of morphine. Transsphenoidal surgery was performed, and histological examination revealed an aspect of hypophysitis. One month later, clinical reexamination showed skin and tongue lesions very suggestive of a syphilis infection, which was serologically confirmed. Immunohistochemistry on paraffin sections of the resected pituitary revealed an abundant presence of Treponema pallidum, confirming the diagnosis of a syphilitic hypophysitis. Intravenous therapy by benzylpenicillin for 14 days was rapidly efficient. Headaches stopped within a few days, and the skin and tongue lesions disappeared during the following month. Thyrotropic deficiency resolved in 2 weeks, but partial corticotropic deficiency persisted at 3 months. Conclusion: This is the first case of a pituitary involvement in acquired syphilis, pathologically proven, in a non-HIV-infected patient. In a context of the resurgence of syphilis, this diagnosis should be considered in the case of a pituitary lesion with unusually intense headaches. Copyright © 2015 by the Endocrine Society.

Vezzosi D.,University of Paris Descartes | Vezzosi D.,Center Hospitalier University Larrey | Vezzosi D.,University Paul Sabatier | Vezzosi D.,French Institute of Health and Medical Research | And 31 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2015

Context: Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTHindependent Cushing's syndrome that may occur in an isolated form or as part of Carney complex. The diagnosis of this disease can be difficult preoperatively because computed tomography (CT) scan can be normal or suggest unilateral adrenal lesion, which can impede the correct diagnosis of bilateral adrenal disease. Objective: The aim of our study was to describe the results of preoperative imaging (adrenal [6β-131I]iodomethyl-19-norcholesterol] [NP-59] scintigraphy and standard adrenal CT scan) and their correlations with clinical, pathological, and genetics investigations in patients with PPNAD. Patients and Methods: Seventeen patients with ACTH-independent syndrome due to PPNAD were investigated with a standard adrenal CT scan and NP-59 scintigraphy. Hormonal, pathological, and genetics data were analyzed. Results: Four males and 13 females (median age, 27 y) were included. PPNAD was isolated in 11 patients (with PRKAR1A mutation, n = 7; and without PRKAR1A mutation, n = 4) and was associated with extra-adrenal manifestations of Carney complex in six patients (with PRKAR1A mutation, n=4; and without PRKAR1A mutation, n=2). Standard adrenal CT scan revealed micronodules in 11 patients, macronodules in three patients, and was normal in three patients. All patients demonstrated bilateral adrenal radiocholesterol uptake. Adrenal uptake was asymmetrical in 10 of 17 patients (59%). Asymmetrical uptake correlated with the presence of macronodules at pathological analysis (P = .03). Conclusion: Standard adrenal CT scan most often reveals micronodules but there is no specific CT imaging. NP-59 scintigraphy always shows a bilateral adrenal uptake confirming the bilateral nature of the disease, but asymmetrical scintigraphic uptake can be observed in patients with macronodules. Copyright © 2015 by the Endocrine Society.

Zheng S.,University of Houston | Cherniack A.D.,The Broad Institute of MIT and Harvard | Cherniack A.D.,Dana-Farber Cancer Institute | Dewal N.,Baylor College of Medicine | And 53 more authors.
Cancer Cell | Year: 2016

We describe a comprehensive genomic characterization of adrenocortical carcinoma (ACC). Using this dataset, we expand the catalogue of known ACC driver genes to include PRKAR1A, RPL22, TERF2, CCNE1, and NF1. Genome wide DNA copy-number analysis revealed frequent occurrence of massive DNA loss followed by whole-genome doubling (WGD), which was associated with aggressive clinical course, suggesting WGD is a hallmark of disease progression. Corroborating this hypothesis were increased TERT expression, decreased telomere length, and activation of cell-cycle programs. Integrated subtype analysis identified three ACC subtypes with distinct clinical outcome and molecular alterations which could be captured by a 68-CpG probe DNA-methylation signature, proposing a strategy for clinical stratification of patients based on molecular markers. Zheng et al. perform comprehensive genomic characterization of 91 cases of adrenocortical carcinoma (ACC). This analysis expands the list of driver genes in ACC, reveals whole-genome doubling as a hallmark of ACC progression, and identifies three ACC subtypes with distinct clinical outcome. © 2016 Elsevier Inc.

Lefevre L.,French Institute of Health and Medical Research | Lefevre L.,French National Center for Scientific Research | Lefevre L.,University of Paris Descartes | Omeiri H.,French Institute of Health and Medical Research | And 33 more authors.
Oncogenesis | Year: 2015

Adrenocortical cancer (ACC) is a very aggressive tumor, and genomics studies demonstrate that the most frequent alterations of driver genes in these cancers activate the Wnt/β-catenin signaling pathway. However, the adrenal-specific targets of oncogenic β-catenin-mediating tumorigenesis have not being established. A combined transcriptomic analysis from two series of human tumors and the human ACC cell line H295R harboring a spontaneous β-catenin activating mutation was done to identify the Wnt/β-catenin targets. Seven genes were consistently identified in the three studies. Among these genes, we found that AFF3 mediates the oncogenic effects of β-catenin in ACC. The Wnt response element site located at nucleotide position . 1408 of the AFF3 transcriptional start sites (TSS) mediates the regulation by the Wnt/β-catenin signaling pathway. AFF3 silencing decreases cell proliferation and increases apoptosis in the ACC cell line H295R. AFF3 is located in nuclear speckles, which play an important role in RNA splicing. AFF3 overexpression in adrenocortical cells interferes with the organization and/or biogenesis of these nuclear speckles and alters the distribution of CDK9 and cyclin T1 such that they accumulate at the sites of AFF3/speckles. We demonstrate that AFF3 is a new target of Wnt/β-catenin pathway involved in ACC, acting on transcription and RNA splicing.

Drougat L.,University of Paris Descartes | Espiard S.,University of Paris Descartes | Bertherat J.,University of Paris Descartes | Bertherat J.,Referral Center for Rare Adrenal Diseases
European Journal of Endocrinology | Year: 2015

Long-term consequences of cortisol excess are frequent despite appropriate treatment after cure of Cushing's syndrome. This might be due to diagnostic delay, often difficult to reduce in rare diseases. The identification of a genetic predisposing factor might help to improve early diagnosis by familial screening. Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing's syndrome. Hypercortisolism in PBMAH is most often diagnosed between the fifth and sixth decades of life. The bilateral nature of the adrenocortical tumors and the occurrence of rare clear familial forms suggest a genetic origin. Indeed, a limited subset of PBMAH can be observed as part of multiple tumors syndromes due to alterations of the APC, Menin or Fumarate Hydratase genes. Rare variants of the phosphodiesterases PDE11A have been associated with PBMAH. The recent identification of ARMC5 germline alterations in 25-50% of PBMAH patients without obvious familial history or associated tumors opens new perspectives. ARMC5 alterations follow the model of a tumor suppressor gene: a first germline inactivating mutation of this 16p located gene is followed by a somatic secondary hit on the other allele (inactivating mutation or allelic loss). Functional studies demonstrate that ARMC5 controls apoptosis and steroid synthesis. The phenotype of index cases patients with the mutation seems more severe than the one of WTindex cases. However, phenotype variability within a family is often observed. This review summarizes the genetics of PBMAH, focusing on ARMC5, which offer new perspectives for early diagnosis of Cushing's syndrome. © 2015 European Society of Endocrinology.

Assie G.,Referral Center for Rare Adrenal Diseases | Assie G.,University of Paris Descartes | Jouinot A.,University of Paris Descartes | Bertherat J.,Referral Center for Rare Adrenal Diseases | Bertherat J.,University of Paris Descartes
Nature Reviews Endocrinology | Year: 2014

Pan-genomic analyses of genetic and epigenetic alterations and gene expression profiles are providing important new insights into the pathogenesis and molecular classification of cancers. The technologies and methods used for these studies are rapidly diversifying and improving. The use of such methodologies for the analysis of adrenocortical tumours has revealed clear transcriptomic (mRNA and microRNA expression profiles), epigenomic (DNA methylation profiles) and genomic (DNA mutations and chromosomal alterations) differences between benign and malignant tumours. Interestingly, genomic studies of adrenal cancers have also identified subtypes of malignant tumours, which demonstrate distinct patterns of molecular alterations and are associated with different clinical outcomes. These discoveries have created the opportunity for classifying adrenocortical tumours on the basis of molecular analyses. Following these genomic studies, efforts to develop new molecular tools that improve diagnosis and prognostication of patients with adrenocortical tumours have also been made. This Review describes the progress that has been made towards classification of adrenocortical tumours to date based on key genomic approaches. In addition, the potential for the development and use of various molecular tools to personalize the management of patients with adrenocortical tumours is discussed.

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