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Introduction Osilodrostat is a new 11β-hydroxylase inhibitor with a mode of action analogous to Metyrapone. The objective of this study was to compare steroidogenic profiles in patients treated with either Osilodrostat or Metyrapone for adrenocorticotrophic hormone (ACTH)-dependent Cushing's syndrome (CS). Methods Patients followed up at Cochin hospital Endocrinology department between March 2019 and December 2021 for an ACTH-dependent CS, controlled by either Osilodrostat or Metyrapone, were included. A serum profile of five steroids (cortisol, 11-deoxycortisol, 17-hydroxyprogesterone, androstenedione and testosterone) was determined using UPLC- tandem mass spectrometry (UPLC-MS/MS). Results Nineteen patients treated with Osilodrostat, eight patients treated with Metyrapone and six patients treated with consecutive Metyrapone then Osilodrostat were included. Hypocortisolism (basal cortisol Conclusion In patients with ACTH-dependent CS, the use of CYP11B1 inhibitors in routine care suggests that Osilodrostat has a less specific effect on the inhibition of steroidogenic enzymes than Metyrapone. This might explain a smaller increase in 11-deoxycortisol and androgen levels in patients treated with Osilodrostat.

Objective Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a heterogeneous disease characterized by adrenal macronodules and variable levels of cortisol excess, with not clearly established clinical diagnostic criteria. It can be caused by ARMC5 germline pathogenic variants. In this study, we aimed to identify predictive criteria for ARMC5 variants. Methods We included 352 consecutive index patients from 12 European centers, sequenced for germline ARMC5 alteration. Clinical, biological and imaging data were collected retrospectively. Results 52 patients (14.8%) carried ARMC5 germline pathogenic variants and showed a more distinct phenotype than non-mutated patients for cortisol excess (24-h urinary free cortisol 2.32 vs 1.11-fold ULN, respectively, P < 0.001) and adrenal morphology (maximal adrenal diameter 104 vs 83 mm, respectively, P < 0.001) and were more often surgically or medically treated (67.9 vs 36.8%, respectively, P < 0.001). ARMC5-mutated patients showed a constant, bilateral adrenal involvement and at least a possible autonomous cortisol secretion (defined by a plasma cortisol after 1 mg dexamethasone suppression above 50 nmol/L), while these criteria were not systematic in WT patients (78.3%). The association of these two criteria holds a 100% sensitivity and a 100% negative predictive value for ARMC5 pathogenic variant. Conclusion We report the largest series of index patients investigated for ARMC5 and confirm that ARMC5 pathogenic variants are associated with a more severe phenotype in most cases. To minimize negative ARMC5 screening, genotyping should be limited to clear bilateral adrenal involvement and autonomous cortisol secretion, with an optimum sensitivity for routine clinical practice. These findings will also help to better define PBMAH diagnostic criteria.

IntroductionDiagnosis of endogenous hyperinsulinism relies on the occurrence of a hypoglycemia, concomitant with inadequate high insulin and C-peptide levels. However, diagnostic cutoffs are not consensual among the different learned societies. The objective of this work was to propose optimized cutoffs for these three parameters for the diagnosis of endogenous hyperinsulinism.MethodsAll the patients having performed a fasting trial in Cochin Hospital Endocrinology Department between February 2012 and August 2022 were included. The results of glycemia, insulin and C-peptide levels during fasting trial were collected and analyzed.ResultsOne hundred and fifty-nine patients were included: 26 with endogenous hyperinsulinism and 133 without endogenous hyperinsulinism. ROC analysis of glycemia nadir during fasting trial identified the value of 2.3 mmol/L as the optimal cutoff, ensuring a sensitivity of 100% associated with a specificity of 81%. ROC analysis of insulin and C-peptide levels concomitant with hypoglycemia ConclusionA C-peptide level 0.3 nmol/L concomitant with a hypoglycemia

Adrenogenital syndrome is commonly associated with a deficiency in 21-hydroxylase but can be present in other rare enzymatic blocks. We report here the case of a 31-year-old man who presented with bilateral painful testicle lesions leading to bilateral partial orchiectomy as they were suspected for malignancy. These lesions were finally identified as benign testicle adrenal rest tumors (TARTs), and the patient was actually belatedly diagnosed with primary adrenal insufficiency due to 2 mutations of the CYP11A1 gene encoding the cholesterol side-chain cleavage enzyme (P450scc); the mutations were 940G > A (p.Glu314Lys) and c.1393C > T (p.Arg465Trp). The same mutations were found in his 29-year-old sister, who was then also diagnosed for primary adrenal insufficiency. Deficiency in P450scc is an extremely rare genetic autosomal recessive disorder with around 40 described families in the literature and 30 different mutations. As the diagnosis of delayed onset of P450Scc mutation is difficult, this case illustrates the need for a systematic endocrinological assessment in any case of bilateral testicle lesions, thus avoiding unnecessary surgery.

Context Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease caused by mutations in the tumor suppressor gene MEN1. The uncertainty of pathogenicity of MEN1 variants complexifies the selection of the patients likely to benefit from specific care. Objective MEN1-mutated patients should be offered tailored tumor screening and genetic counseling. We present a patient with hyperparathyroidism for whom genetic analysis identified a variant of uncertain significance in the MEN1 gene (NM_130799.2): c.654G > T p.(Arg218=). Additional functional genetic tests were performed to classify the variant as pathogenic and allowed prenatal testing. Design Targeted next generation sequencing identified a synonymous variant in the MEN1 gene in a 26-year-old male with symptomatic primary hyperparathyroidism. In silico and in vitro genetic tests were performed to assess variant pathogenicity. Results Genetic testing of the proband’s unaffected parents showed the variant occurred de novo. Transcript study showed a splicing defect leading to an in-frame deletion. The classification of the MEN1 variant as pathogenic confirmed the diagnosis of MEN1 and recommended an adapted medical care and follow-up. Pathogenic classification also allowed to propose a genetic counseling to the proband and his wife. Noninvasive prenatal diagnosis was performed with a personalized medicine-based protocol by detection of the paternally inherited variant in maternal plasmatic cell free DNA, using digital PCR. Conclusion We showed that functional genetic analysis can help to assess the pathogenicity of a MEN1 variant with crucial consequences for medical care and genetic counseling decisions.

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 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.

biBackground:/i/bNuclear protein in testis (NUT) carcinomas (NC) are a rare, highly aggressive, subset of squamous cell carcinomas, characterized by a translocation involving theiNUTM1/igene. Thyroid location of NUT carcinomas has rarely been described.biMethods:/i/bWe report here two cases of thyroid NC withiNSD3::NUTM1/itranslocation.biResults:/i/bThe first case presented as a very aggressive undifferentiated thyroid carcinoma in a 38-year-old man who died 21 months after the diagnosis. The second case was diagnosed after multiple lymphadenopathy recurrences mainly in the neck in a 37-year-old woman 7 years after total thyroidectomy for papillary thyroid carcinoma with a classic and a solid/trabecular component.biConclusions:/i/bOur case reports highlight the challenges in diagnosing these exceptional carcinomas. The therapeutic impact of the administration of pharmacological compounds with epigenetic action, in line with the physiopathology of these carcinomas, is also discussed.

Amiodarone-induced thyrotoxicosis (AIT) are not uncommon endocrinopathies. Clinicians are sometimes faced with difficult diagnostic and therapeutic situations. The disease pathophysiology is partially understood, explaining the lack of predictive factors for occurrence. Different international recommendations for their management have been published: the most recent in 2018 by the European Thyroid Association (ETA) (Ross et al., 2016; Bartalena et al., 2018). The purpose of this paper is to present the essential concepts for their management and to review the literature since 2018.

Introduction Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) is a heterogeneous disease characterized by bilateral adrenal macronodules responsible for adrenal Cushing. To date, two genetic causes of PBMAH are known: germline inactivating variants of the tumor suppressor genes ARMC5 identified in 2013 (Assié, N Eng J Med 2013), responsible for 20 to 25% of index cases, and KDM1A, identified recently (Vaczlavik, GIM 2021; Chasseloup, Lancet D&E 2021), responsible for the rare presentation associated with food-dependent Cushing's syndrome (FDCS) due to aberrant expression of the GIP receptor (GIPR) in adrenocortical cells. Multiple other illegitimate receptors are known to be responsible for abnormal cortisol response to various physiological stimuli in PBMAH. A recent multiomic analysis, identified three distinct molecular PBMAH groups: G1 with ARMC5-mutated tumors, G2 with KDM1A-mutated tumors from FDCS patients, and G3 with no identified genetic cause at present. We aimed to identify specific expression profiles of illegitimate receptors in the three groups. Methods Based on the transcriptome data obtained by RNA sequencing (Illumina) of the tumors from 31 patients (G1/ARMC5, 16 patients; G2/KDM1A, 6 patients; G3, 9 patients), expression of the following genes, encoding potential illegitimate receptors, were compared: ADRA1A, ADRA1B, ADRA1D, ADRA2A, ADRA2B, ADRA2C, ADRB1, ADRB2, ADRB3, AVPR1A, AVPR1B, AVPR2, GCGR, GIPR, HTR4, HTR7, LHCGR. Calculations were performed using R statistical software. The Bioconductor limma package was used to analyze mRNA differential expression. Results G1/ARMC5 tumors showed a relative overexpression of the vasopressin receptors AVPR1A and AVPR1B compared to the two other groups (fold-change [FC] =7.39, p Conclusion This study reveals specific expression profiles of illegitimate receptors related to the three molecular groups. ARMC5 tumors are associated with the overexpression of two vasopressin receptors, while, besides GIPR, KDM1A inactivation seems to drive the overexpression of the LH/hCG receptor, as previously suggested in patients with FDCS (Bertherat, JCE&M 2005), potentially responsible for Cushing's syndrome associated with pregnancy and menopause. These molecular patterns need to be corroborated by clinical data with a systematic testing of the aberrant cortisol responses. Additionally, further studies would be needed to investigate the clinical relevance and significance of moderate fold-changes in gene expression (e.g. Presentation: Saturday, June 11, 2022 12:00 p.m. - 12:15 p.m.

Annales d'Endocrinologie - In Press. Accepted Manuscript Available online since lundi 4 mai 2020

Patients affected by pseudohypoparathyroidism (PHP) or related disorders are characterized by physical findings that may include brachydactyly, a short stature, a stocky build, early-onset obesity, ectopic ossifications, and neurodevelopmental deficits, as well as hormonal resistance most prominently to parathyroid hormone (PTH). In addition to these alterations, patients may develop other hormonal resistances, leading to overt or subclinical hypothyroidism, hypogonadism and growth hormone (GH) deficiency, impaired growth without measurable evidence for hormonal abnormalities, type 2 diabetes, and skeletal issues with potentially severe limitation of mobility. PHP and related disorders are primarily clinical diagnoses. Given the variability of the clinical, radiological, and biochemical presentation, establishment of the molecular diagnosis is of critical importance for patients. It facilitates management, including prevention of complications, screening and treatment of endocrine deficits, supportive measures, and appropriate genetic counselling. Based on the first international consensus statement for these disorders, this article provides an updated and ready-to-use tool to help physicians and patients outlining relevant interventions and their timing. A life-long coordinated and multidisciplinary approach is recommended, starting as far as possible in early infancy and continuing throughout adulthood with an appropriate and timely transition from pediatric to adult care.

Design Molecular classification is important for the diagnosis and prognosis of adrenocortical tumors (ACT). Transcriptome profiles separate adrenocortical adenomas ‘C2’ from carcinomas, and identify two groups of carcinomas ‘C1A’ and ‘C1B’, of poor and better prognosis respectively. However, many ACT cannot be profiled because of improper or absent freezing procedures, a mandatory requirement so far. The main aim was to determine transcriptome profiles on formalin-fixed paraffin-embedded (FFPE) samples, using the new 3’-end RNA-sequencing technology. A secondary aim was to demonstrate the ability of this technique to explore large FFPE archives, by focusing on the rare oncocytic ACT variants. Methods We included 131 ACT: a training cohort from Cochin hospital and an independent validation cohort from Wuerzburg hospital. The 3’ transcriptome was generated from FFPE samples using QuantSeq (Lexogen, Vienna, Austria) and NextSeq500 (Illumina, San Diego, CA, USA). Results In the training cohort, unsupervised clustering identified three groups: ‘C1A’ aggressive carcinomas (n = 28, 29%), ‘C1B’ more indolent carcinomas (n = 28, 29%), and ‘C2’ adenomas (n = 39, 41%). The prognostic value of FFPE transcriptome was confirmed in the validation cohort (5-year OS: 26% in ‘C1A’ (n = 26) and 100% in ‘C1B’ (n = 10), P = 0.003). FFPE transcriptome was an independent prognostic factor in a multivariable model including tumor stage and Ki-67 (OS HR: 7.5, P = 0.01). Oncocytic ACT (n = 19) did not form any specific cluster. Oncocytic carcinomas (n = 6) and oncocytic ACT of uncertain malignant potential (n = 4) were all in ‘C1B’. Conclusions The 3’ RNA-sequencing represents a convenient solution for determining ACT molecular class from FFPE samples. This technique should facilitate routine use and large retrospective studies.

Background. Metastatic thyroid cancers may dedifferentiate and become radioactive iodine refractory. The redifferentiating effect of pharmacological drugs was reported with inhibitors of the MAPK p...

Background: Cardiac metastases from thyroid cancers are uncommon with a poor prognosis. There is a lack of long-term follow-up studies. Cases: We report 2 cases of cardiac metastasis from medullary thyroid cancer (MTC). Both patients presented limited metastatic disease apart from a cardiac metastasis. The initial diagnosis was challenging and was facilitated by functional imaging with an immuno-PET-CT using an anti-CEA bispecific antibody and a 68Ga-labeled peptide. Both patients were treated with the multitarget kinase inhibitor vandetanib with prolonged stability. The first patient was alive at the last follow-up, 14 years after the diagnosis of cardiac metastasis. The second patient required surgical excision of the cardiac mass because of disease progression under vandetanib. Conclusion: These cases illustrate long-term survival and effectiveness of clinical management of 2 patients who developed cardiac metastases from MTC, in the current era of personalized medicine with targeted therapy.

Benign adrenal tumors cover a spectrum of lesions with distinct morphology and steroid secretion. Current classification is empirical. Beyond a few driver mutations, pathophysiology is not well understood. Here, a pangenomic characterization of benign adrenocortical tumors is proposed, aiming at unbiased classification and new pathophysiological insights. Benign adrenocortical tumors (n = 146) were analyzed by transcriptome, methylome, miRNome, chromosomal alterations and mutational status, using expression arrays, methylation arrays, miRNA sequencing, SNP arrays, and exome or targeted next-generation sequencing respectively. Pathological and hormonal data were collected for all tumors. Pangenomic analysis identifies four distinct molecular categories: (1) tumors responsible for overt Cushing, gathering distinct tumor types, sharing a common cAMP/PKA pathway activation by distinct mechanisms; (2) adenomas with mild autonomous cortisol excess and non-functioning adenomas, associated with beta-catenin mutations; (3) primary macronodular hyperplasia with ARMC5 mutations, showing an ovarian expression signature; (4) aldosterone-producing adrenocortical adenomas, apart from other benign tumors. Epigenetic alterations and steroidogenesis seem associated, including CpG island hypomethylation in tumors with no or mild cortisol secretion, miRNA patterns defining specific molecular groups, and direct regulation of steroidogenic enzyme expression by methylation. Chromosomal alterations and somatic mutations are subclonal, found in less than 2/3 of cells. New pathophysiological insights, including distinct molecular signatures supporting the difference between mild autonomous cortisol excess and overt Cushing, ARMC5 implication into the adreno-gonadal differentiation faith, and the subclonal nature of driver alterations in benign tumors, will orient future research. This first genomic classification provides a large amount of data as a starting point.

Introduction Carney Complex (CNC) is a rare multiple endocrine and nonendocrine neoplasia syndrome. Manifestations and genotype-phenotype correlations have been described by retrospective studies, but no prospective study evaluating the occurrence of the different manifestations has been available so far. Methods This multicenter national prospective study included patients with CNC, primary pigmented nodular adrenal disease (PPNAD), or a pathogenic PRKAR1A mutation; after a full initial workup, participants were followed for 3 years with annual standardized evaluation. Results The cohort included 70 patients (50 female/20 male, mean age 35.4 ± 16.7 years, 81% carrying PRKAR1A mutation). The initial investigations allowed identification of several manifestations. At the end of the 3-year follow-up, the newly diagnosed manifestations of the disease were subclinical acromegaly in 6 patients, bilateral testicular calcifications in 1 patient, and cardiac myxomas in 2 patients. Recurrences of cardiac myxomas were diagnosed in 4 patients during the 3-year follow-up study period. Asymptomatic abnormalities of the corticotroph and somatotroph axis that did not meet criteria of PPNAD and acromegaly were observed in 11.4% and 30% of the patients, respectively. Patients carrying the PRKAR1A c.709-7del6 mutation had a mild phenotype. Conclusion This study underlines the importance of a systematic follow-up of the CNC manifestations, especially a biannual screening for cardiac myxoma. By contrast, regular screening for the other manifestations after a first extensive workup could be spread out, leading to a lighter and more acceptable follow-up schedule for patients. These are important results for recommendations for long-term management of CNC patients.

Background: The prognosis of adrenocortical carcinoma (ACC) is heterogeneous. Genomic studies have identified ACC subgroups characterized by specific molecular alterations, including features measured at DNA level (somatic mutations, chromosome alterations, DNA methylation), which are closely associated with outcome. The aim of this study was to evaluate intratumor heterogeneity of prognostic molecular markers at the DNA level. Methods: Two different tissue samples (primary tumor, local recurrence or metastasis) were analyzed in 26 patients who underwent surgery for primary or recurrent ACC. DNA-related biomarkers with prognostic role were investigated in frozen and paraffin-embedded samples. Somatic mutations of p53/Rb and Wnt/β-catenin pathways were assessed using next-generation sequencing (n = 26), chromosome alteration profiles were determined using SNP arrays (n = 14) and methylation profiles were determined using four-gene bisulfite pyrosequencing (n = 12). Results: Somatic mutations for ZNRF3, TP53, CTNN1B and CDKN2A were found in 7, 6, 6 and 4 patients, respectively, with intratumor heterogeneity in 8/26 patients (31%). Chromosome alteration profiles were ‘Noisy’ (numerous and anarchic alterations) in 8/14 and ‘Chromosomal’ (extended patterns of loss of heterozygosity) in 5/14 of the study samples. For these profiles, no intratumor heterogeneity was observed. Methylation profiles were hypermethylated in 5/12 and non-hypermethylated in 7/12 of the study samples. Intratumor heterogeneity of methylation profiles was observed in 2/12 patients (17%). Conclusions: Intratumor heterogeneity impacts DNA-related molecular markers. While somatic mutation can differ, prognostic DNA methylation and chromosome alteration profile seem rather stable and might be more robust for the prognostic assessment.

The management of radioiodine refractory thyroid cancers (RAIR TC) is challenging for the clinician. Tyrosine kinase inhibitors classically prescribed in this setting can fail due to primary or acquired resistance or the necessity of drug withdrawal because of serious or moderate but chronic and deleterious adverse effects. Thus, the concept of redifferentiation strategy, which involves treating patients with one or more drugs capable of restoring radioiodine sensitivity for RAIR TC, has emerged. The area of redifferentiation strategy leads to the creation of new definitions of RAIR TC including persistent non radioiodine-avid patients and ‘true’ RAIR TC patients. The latter group presents a restored or increased radioiodine uptake in metastatic lesions but with no radiological response on conventional imaging, that is, progression of a metastatic disease, thus proving that they are ‘truly’ resistant to the radiation delivered by radioiodine. Unlike these patients, metastatic TC patients with restored radioiodine uptake offer the hope of prolonged remission or even cure of the disease as for radioiodine-avid metastatic TC. Here, we review the different redifferentiation strategies based on the underlying molecular mechanism leading to the sodium iodide symporter (NIS) and radioiodine uptake reinduction, that is, by modulating signaling pathways, NIS transcription, NIS trafficking to the plasma membrane, NIS post-transcriptional regulation, by gene therapy and other potential strategies. We discuss clinical trials and promising preclinical data of potential future targets.

Objectif La regulation de la steroidogenese dans les tumeurs bilaterales de la corticosurrenale est peu decrite dans la litterature. Notre objectif etait d’etudier l’amplitude de reponse a l’ACTH des glucocorticoides et de leurs precurseurs dans les tumeurs surrenaliennes bilaterales. Materiels et methodes Trente-sept patients porteurs de tumeurs surrenaliennes bilaterales (BL), 38 patients atteints de tumeurs unilaterales (UL), et 37 controles (CT), ayant beneficie d’un test au synacthene entre decembre 2018 et mars 2021, ont ete inclus. Quatre steroides consecutifs sur l’axe des glucocorticoides (progesterone > 17OHprogesterone > 11-desoxycortisol > cortisol) ont ete doses en LC-MS/MS sur le T0 et le T60 du test au synacthene. Le volume surrenalien global a ete quantifie dans les BL et les UL a partir des scanners surrenaliens selon une methode de segmentation manuelle. Resultats L’amplitude de reponse des 4 steroides etudies, mesuree par le ratio T60/T0, etait superieure dans les BL par rapport aux CT et aux UL, l’amplitude de reponse des precurseurs (17OHP, 11-desoxycortisol) etant superieure a celle du cortisol. La difference entre les BL et les UL disparaissait apres normalisation de l’amplitude par le volume surrenalien. L’activite enzymatique de la CYP11B1, mesuree par le ratio cortisol/11-desoxycortisol au T60 etait diminuee dans les BL par rapport aux CT (78,3 versus 186,8, P Discussion L’activite de la CYP11B1, etape limitante de la voie de biosynthese du cortisol, est diminuee dans les tumeurs BL pour compenser l’augmentation de la masse surrenalienne.

Introduction Peu d’informations existent sur la prise en charge de l’hypoparathyroidie chronique en vie reelle. Notre objectif est d’etudier l’adequation des pratiques (suivi et objectifs du traitement) avec les recommandations internationales. Methodes Nous utilisons les donnees d’un sous-groupe de la e-cohorte francaise Epi-Hypo (118 medecins et 107 patients, 09/2016-12/2019) et celles d’une enquete en ligne (110 ePatients, 11/2019). Les participants devaient etre i) medecin prenant en charge des patients avec hypoparathyroidie chronique ou ii) patient participant a la cohorte Epi-Hypo ou iii) patient de l’association Hypoparathyroidisme France (ePatients). Resultats Endocrinologues et nephrologues representent 89 % des medecins mais d’autres specialites sont aussi impliquees. L’association vitamine D active/sels de calcium est donnee a 58-59 % des patients. La majorite (85-87 %) des medecins suit la calcemie au moins 2 fois/an a l’etat stable. Les recommandations internationales conseillent de controler les symptomes, les valeurs de calcemie, de phosphatemie et de calciurie : un controle simultane de tous ces facteurs est rapporte par 32 % des ePatients et 26 % des medecins. La majorite (80 %) des ePatients rapportent que leurs symptomes sont insuffisamment controles par le traitement en cours alors que leur suivi est similaire a ceux dont les symptomes sont controles. Leur traitement est similaire en dehors des sels de magnesium qu’ils recoivent plus frequemment que les autres. Discussion De nombreuses specialites sont impliquees dans la prise en charge des patients avec hypoparathyroidie chronique en France : les recommandations devraient les cibler car l’adherence est encore faible. De nouveaux traitements sont necessaires pour mieux controler les symptomes.

Objectif L’epreuve de jeune reste la methode de reference pour confirmer le diagnostic d’insulinome sur la survenue d’une hypoglycemie associee a des taux d’insuline et de peptide C eleves inadaptes. Neanmoins, les valeurs seuils retenues pour le diagnostic ne sont pas consensuelles et la determination de l’insulinemie peut etre mise en defaut en cas de prelevement hemolyse. Materiels et methodes Nous avons analyse de maniere retrospective les resultats des epreuves de jeune des 132 patients hospitalises dans le service d’Endocrinologie de l’Hopital Cochin entre fevrier 2012 et decembre 2020. Les resultats sont exprimes en mediane (minimum-maximum). Resultats Le diagnostic d’hyperinsulinisme endogene (HE) a ete pose chez 21 des 132 patients etudies: 20 cas d’insulinomes et un cas d’HE congenital. Le nadir de glycemie etait plus bas dans le groupe HE 1,8 (1,28–2,3) mmol/L versus 2,93 (1,47–4,85) mmol/L (p 0,2 nmol/L permettaient de poser le diagnostic d’HE avec une sensibilite de 100 % et une specificite de 98 %. Discussion Un seuil de glycemie ≤ 2,3 mmol/L et de C-peptide > 0,2 nmol/L sans critere sur l’insulinemie donnent de meilleures performances diagnostiques que les recommandations actuelles pour le diagnostic d’HE.

Introduction: Checkpoint inhibitors have significantly improved the prognosis of patients with advanced melanoma. These cancer immunotherapy drugs have specific endocrine autoimmune toxicity. We describe a case of an adrenal insufficiency secondary to pembrolizumab, an anti-programmed cell death-1 monoclonal antibody. Moreover, this case of polyendocrinopathy resulting from a pembrolizumab as the adrenal insufficiency occurred after a thyroiditis. Participant: A 55-year-old female was started on pembrolizumab immunotherapy for a metastatic choroidal melanoma. Five months after initiation, she suffered from thyrotoxicosis. A thyroiditis was diagnosed by iodine-123 thyroid scintigraphy and ultrasonography. Pembrolizumab therapy was maintained. Two weeks later, without any other treatment given, she patient developed hypothyroidism and levothyroxine substitution was started. Pembrolizumab proved to be ineffective and was stopped 9 months after initiation. One month following its discontinuation, the patient was hospitalized in the intensive care unit. Severe hyponatremia (115 mmol/L) associated with hyperkalemia (5.7 mmol/L) led to the early recognition and treatment of an acute adrenal insufficiency. Positive results for adrenal cortex and 21-hydroxylase antibodies were in favor of autoimmune toxicity. Conclusion: This case highlights the diversity of potential endocrine toxicity of checkpoint inhibitors. Because acute adrenal crisis may be associated with substantial morbidity and mortality, physicians must be aware of these rare adverse events to allow an early diagnosis., We present a case of adrenal insufficiency secondary to pembrolizumab and of polyendocrinopathy secondary to pembrolizumab.

Context: Adrenocortical carcinomas (ACCs) are revealed in 60% of cases by steroid hypersecretion. Alternatively, it is uncommon to observe a paraneoplastic syndrome due to a peptide oversecretion. Case Description: We describe a 60-year-old man with a right adrenal mass. Hormonal evaluation showed an ACTH-independent Cushing syndrome. Surprisingly, follicle-stimulating hormone (FSH) levels were suppressed and blunted during gonadotropin-releasing hormone stimulation, despite normal luteinizing hormone levels. Levels of inhibin B, which negatively regulates the pituitary FSH, were very high. Given the atypical hormonal findings, an adrenal mass biopsy was performed, which allowed the diagnosis of an adrenocortical tumor (positive for steroidogenic factor-1 immunostaining). Moreover, an intense α-inhibin subunit immunostaining was observed. Because of the presence of metastases, the patient received mitotane and chemotherapy (etoposide and cisplatin). After 2 cycles, the inhibin B dropped. After 5 cycles, tumor size was reduced by 15%. Inhibin B levels remained low, and basal and gonadotropin-releasing hormone–stimulated FSH levels normalized. The patient underwent tumor resection, and pathology confirmed the ACC diagnosis (Weiss score of 9). The intensity of the α-inhibin subunit immunostaining was significantly decreased. Conclusions: We report the case of an inhibin B–secreting ACC in which the response to chemotherapy and mitotane was associated with a normalization of inhibin B secretion, allowing the reversal of the blunted FSH secretion. Inhibin B should be measured in case of suppressed FSH levels despite normal luteinizing hormone levels and may be considered a tumoral marker in some ACCs, even during treatment follow-up., Precis: We studied an adrenal mass with suppressed FSH levels, blunted after GnRH stimulation, and found an inhibin B–secreting adrenocortical carcinoma, in which inhibin B was normalized after chemotherapy.

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This image illustrates a multimodal therapeutic strategy for an iodine-refractory BRAF-mutated metastatic papillary thyroid carcinoma with reversed radioiodine resistance using BRAF inhibitors.

Precis: We report the unusual etiology of a sellar aggressive mass, an epithelioid angiosarcoma, the diagnosis of which was made from positive epithelial and vascular markers.

La neoplasie endocrine multiple de type 1 (NEM1) est une maladie genetique rare, de transmission autosomique dominante, due a une mutation heterozygote inactivatrice du gene codant pour la menine. La NEM1 a une penetrance quasiment complete, avec une expressivite variable. L’hyperparathyroidie primaire est la manifestation la plus frequente, presente chez la plupart des patients a l’âge de 50 ans. Les tumeurs neuroendocrines pancreatiques et les adenomes hypophysaires sont les autres atteintes les plus frequentes a depister au cours du suivi. Les tumeurs endocrines thymiques sont plus rares, mais posent des questions specifiques de depistage et de traitement. Au cours des dernieres annees la connaissance de cette maladie a progresse, notamment grâce aux donnees de differents registres. Nous allons aborder les dernieres actualites concernant la prise en charge des principales manifestations, en insistant sur les nouvelles approches diagnostiques en imagerie fonctionnelle et les nouvelles pistes de traitement preventif ou curatif.

This Consensus Statement covers recommendations for the diagnosis and management of patients with pseudohypoparathyroidism (PHP) and related disorders, which comprise metabolic disorders characterized by physical findings that variably include short bones, short stature, a stocky build, early-onset obesity and ectopic ossifications, as well as endocrine defects that often include resistance to parathyroid hormone (PTH) and TSH. The presentation and severity of PHP and its related disorders vary between affected individuals with considerable clinical and molecular overlap between the different types. A specific diagnosis is often delayed owing to lack of recognition of the syndrome and associated features. The participants in this Consensus Statement agreed that the diagnosis of PHP should be based on major criteria, including resistance to PTH, ectopic ossifications, brachydactyly and early-onset obesity. The clinical and laboratory diagnosis should be confirmed by a molecular genetic analysis. Patients should be screened at diagnosis and during follow-up for specific features, such as PTH resistance, TSH resistance, growth hormone deficiency, hypogonadism, skeletal deformities, oral health, weight gain, glucose intolerance or type 2 diabetes mellitus, and hypertension, as well as subcutaneous and/or deeper ectopic ossifications and neurocognitive impairment. Overall, a coordinated and multidisciplinary approach from infancy through adulthood, including a transition programme, should help us to improve the care of patients affected by these disorders, This Consensus Statement and the series of consensus meetings were supported by funds from the European Cooperation in Science and Technology (COST) action BM1208 on imprinting disorders (www.imprinting- disorders.eu), the European Society for Paediatric Endocrinology (ESPE) and the European Society for Endocrinology (ESE). Travel costs and housing of the representatives of the Asian Pacific Paediatric Endocrine Society (APPES) and of the Pediatric Endocrine Society (PES) were supported by their societies. The authors received no funding from pharmaceutical companies

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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.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.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.

ObjectiveManagement of insulinomas in the context of MEN1 remains poorly studied. The aim of this study was to evaluate long-term results of various surgical approaches in a large cohort of insulinoma–MEN1 patients.Design and methodsConsecutive insulinoma–MEN1 patients operated on for a nonmetastatic insulinoma between 1957 and 2010 were retrospectively selected from the MEN1 database of the French Endocrine Tumor Group. The type of surgery was categorized as distal pancreatectomy (DP), total pancreatectomy/cephalic duodenopancreatectomy (TP/CDP), or enucleation (E). Primary endpoint was time until recurrence of hypoglycemia after initial surgery. Secondary endpoints were post-operative complications.ResultsThe study included 73 patients (median age=28 years). Surgical procedures were DP (n=46), TP/CDP (n=9), or E (n=18). After a median post-operative follow-up of 9.0 years (inter-quartile range (IQR): 2.5–16.5 years), 60/73 patients (82.2%) remained hypoglycemia free. E and TP/CDP were associated with a higher risk of recurrent hypoglycemia episodes (unadjusted hazard ratio: 6.18 ((95% CI: 1.54–24.8);P=0.010) for E vs DP and 9.51 ((95% CI: 1.85–48.8);P=0.007) for TP/CDP vs DP. After adjustment for International Union against Cancer pTNM classification, enucleation remained significantly associated with a higher probability of recurrence. Long-term complications had occurred in 20 (43.5%) patients with DP, five (55.6%) with TP/CDP, but in none of the patients who have undergone E (P=0.002).ConclusionIn the French Endocrine database, DP is associated with a lower risk for recurrent hypoglycemia episodes. Due to lower morbidity, E alone might be considered as an alternative.

International audience

Medullary thyroid carcinomas (MTCs) complicated by ectopic Cushing's syndrome (CS) have a poor prognosis, partially due to the difficulty in controlling hypercortisolism by adrenal blocking drugs. Recent reports (including the initial follow-up of this patient) have suggested that tyrosine kinase inhibitors (TKIs) may be a therapeutic option due to an anti-secretory action on ACTH. However, there is a lack of long-term follow-up studies.The case is reported of a 58-year-old man with MTC-related CS resistant to a combination of several anti-cortisolic drugs. Vandetanib, an oral multi-TKI that targets RET in particular, was initiated, and a rapid reversal of the hypercortisolism was observed without any change in tumor size. Vandetanib was briefly interrupted twice, once for 45 days because of side effects and a second time for 10 days to schedule surgical debulking. Each time, plasma cortisol and calcitonin levels increased after TKI withdrawal and were rapidly lowered by vandetanib reintroduction. As described in other cases of CS caused by MTC, a marked ACTH increase after desmopressin stimulation was observed before vandetanib therapy. In contrast, a blunted ACTH response to desmopressin was documented throughout the course of vandetanib treatment. This modulation of the tumoral ACTH production is a strong argument in favor of a TKI anti-secretory action. A left thyroid lobectomy and a modified neck dissection were performed one year after the initiation of vandetanib in order to reduce the tumor mass. An activating M918T RET (c.2753TC) somatic mutation was identified in a lymph node metastasis.Three years and eight months after vandetanib initiation, there was no sign of recurrence of hypercortisolism. This case illustrates the long-term effectiveness of vandetanib in maintaining the control of hypercortisolism in MTC-related CS.

International audience; Context:Adrenocortical cancer (ACC) is an aggressive tumor with a heterogeneous outcome. Prognostic stratification is difficult even based on tumor stage and Ki67. Recently integrated genomics studies have demonstrated that CpG islands hypermethylation is correlated with poor survival.Objective:The goal of this study was to confirm the prognostic value of CpG islands methylation on an independent cohort.Design:Methylation was measured by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA).Setting:MS-MLPA was performed in a training cohort of 50 patients with ACC to identify the best set of probes correlating with disease-free survival (DFS) and overall survival (OS). These outcomes were validated in an independent cohort from 21 ENSAT centers.Patients:The validation cohort included 203 patients (64% women, median age 50 years, 80% localized tumors).Main Outcome Measures:DFS and OS.Results:In the training cohort, mean methylation of 4 genes (PAX5, GSTP1, PYCARD, PAX6) was the strongest methylation marker. In the validation cohort, methylation was a significant prognostic factor of DFS (P < 0.0001) and OS (P < 0.0001). Methylation, Ki67, and ENSAT stage were combined in multivariate models. For DFS, methylation (P = 0.0005) and stage (P < 0.0001) but not Ki67 (P = 0.19) remained highly significant. For OS, methylation (P = 0.0006), stage (P < 0.0001), and Ki67 (P = 0.024) were independent prognostic factors.Conclusions:Tumor DNA methylation emerges as an independent prognostic factor in ACC. MS-MLPA is readily compatible with clinical routine and should enhance our ability for prognostication and precision medicine.

Introduction L’hypoparathyroidie est une secretion insuffisante d’hormone parathyroidienne entrainant une hypocalcemie. Les causes sont chirurgicales, genetiques, auto-immunes, infiltratives, voire « idiopathique ». Les complications peuvent etre fonctionnelles (neuro/musculaires) et/ou par des calcifications des tissus. Les diagnostics et prises en charge impliquent differentes specialites, et il n’existe pas de donnees nationales francaises. Notre objectif est de faire un etat des lieux de l’hypoparathyroidie chronique en France. Methodes Une plateforme de saisie en ligne a permis de collecter anonymement les donnees cliniques et biologiques des patients au diagnostic et au cours du suivi. La plupart des professionnels impliques a ete contacte depuis septembre 2016 via le centre de reference des maladies rares du calcium et du phosphate (OSCAR) et la SFE. Resultats Au 31 mars 2018, 745 patients etaient inclus (femmes : 71 % ; mineurs : 12 %). Le delai entre le premier symptome et le diagnostic etait de 0 a 77 ans. Les causes au moment de l’inclusion etaient chirurgicale (71 %), genetique (9 %), auto-immune (3 %), radiotherapie (1 %) ou non identifiee (16 %). Au diagnostic, la calcemie etait mesuree a 1,80 ± 0,30 mm ; 15 % des patients avaient une insuffisance renale definie par un debit de filtration glomerulaire estime Discussion Epi-Hypo est la premiere etude nationale sur l’hypoparathyroidie. Elle a probablement un biais de recrutement (centres experts) et va etre completee pour refleter la diversite des situations, preciser la prevalence des complications et identifier des pistes d’amelioration dans la prise en charge. Cependant, Epi-Hypo confirme l’importante prevalence des complications renales de l’hypoparathyroidie.

Les corticosurrenalomes ont un pronostic heterogene. Recemment, les etudes de genomique ont identifie 3 sous-groupes de tumeurs caracterises par des alterations moleculaires specifiques. La classification moleculaire peut etre determinee en routine par des marqueurs cibles et ameliore l’evaluation du pronostic. Objectif Evaluer l’heterogeneite intra-tumorale des alterations moleculaires. Patients et methodes Analyse des mutations de 20 genes drivers (NGS cible) et des alterations chromosomiques (puces SNP) dans 2 echantillons tumoraux differents pour 14 patients operes d’un corticosurrenalome : primitif et metastase (n = 9 dont 5 atteintes metachrones), 2 echantillons de volumineux primitif (n = 2) ou 2 echantillons de metastases (n = 3). Resultats Nous avons observe entre 0 et 4 alterations par echantillon parmi les 20 genes drivers, notamment ZNRF3 (25 %), TP53 (21 %), CTNNB1 (18 %), CDKN2A (21 %) et TERT (21 %). Certaines alterations (CDKN2A, CTNNB1, ZNRF3) n’etaient presentes que dans une metastase (n = 3) ou dans un des deux echantillons du primitif (n = 1). L’heterogeneite intra-tumorale n’etait pas associee au stade au diagnostic ou au grade tumoral. Nous avons identifie des profils d’alterations chromosomiques « bruite » (nombreuses cassures anarchiques) pour 67 % et « chromosomal » (pertes d’heterozygotie etendues) pour 33 % des echantillons, similaires pour les 2 echantillons de chaque patient. Discussion Pour 4/14 patients, l’heterogeneite des mutations somatiques evoque la presence de sous-clones tumoraux d’agressivite differente. Cependant, le profil global des alterations chromosomiques reste identique, suggerant une stabilite genetique lors de la progression tumorale dans les corticosurrenalomes par comparaison a d’autres cancers.

Progress in understanding the molecular genetics of thyroid cancer in the last 20 years has accelerated recently with the advent of high-throughput sequencing technologies known as Next-Generation Sequencing. Besides classical molecular abnormalities involving the MAPK (Mitogen Activated Protein Kinase) and PI3K (PhosphoInositide 3-Kinase) pathways that play a key role in follicular-derived thyroid tumorigenesis, new molecular abnormalities have been discovered. The major advances in recent years have been the discovery of new somatic driver gene point mutations (such as RASAL1 [RAS protein activator Like 1] mutations in follicular cancer) and/or mutations that have prognostic value (such as TERT [Telomerase reverse transcriptase] promoter mutations); new chromosomal rearrangements, usually having close connection with exposure to ionizing radiation (such as ALK [Anaplastic Lymphoma Kinase] rearrangements); and deregulation of some gene or microRNA expression representing a molecular signature. Progress made in understanding the molecular mechanisms of thyroid cancer offers new perspectives for the diagnosis of the benign or malignant status of a thyroid nodule, to refine prognosis and offer new perspectives of targeted therapy for radioiodine-refractory cancers.

In low-risk differentiated thyroid cancer (DTC), postoperative (131)I remnant ablation should employ a minimum effective activity; reports increasingly suggest efficacy of low activities, e.g. 1110 MBq/30 mCi. OBJECTIVES, DESIGN, PATIENTS, AND INTERVENTIONS: We retrospectively studied the ablation capability and diagnostic utility of the Minidose protocol, two 740-MBq/20 mCi outpatient administrations, 6-18 months apart, plus related diagnostic procedures, in 160 consecutive (near-) totally thyroidectomized low-risk DTC (pT1/N0-Nx) patients. Successful ablation comprised negative 740-MBq whole-body scintigraphy with cervical uptake below 0.1%, negative stimulated thyroglobulin (STg) (1 ng/ml, negative thyroglobulin antibodies), and negative Doppler ultrasonography (performed around Minidose 2).The study took place at a referral center.Minidose imaging found unsuspected nodal or distant metastases in nine of 160 patients (5.6%). Ablation success rates after one (two) 740-MBq activity (activites) were 75.9% (90.2%) in 145 (132) evaluable imaging-negative patients. Compared with thyroid hormone withdrawal, recombinant human TSH stimulation was associated with higher urinary iodine excretion/creatinine, lower cervical uptake, and more frequent ablation success after the first 740 MBq; success rates no longer differed significantly after both administrations. Patients with STg below 10 ng/ml at Minidose 1 were oftener ablated at Minidose 2 (odds ratio=13.9, 95% confidence interval=2.5-76.4, P0.003), attaining 92.0% final ablation success after recombinant human TSH preparation, suggesting that one 740-MBq activity should suffice in this subgroup. All 81 evaluable patients with prolonged follow-up (mean 41.8±21.9 months after Minidose 1) had no evidence of disease at the last visit.The Minidose outpatient ablation protocol is effective and diagnostically useful in low-risk DTC.

Le traitement de premiere intention des adenomes thyreotropes est l’adenomectomie chirurgicale. Une alternative therapeutique repose sur les SMSa de premiere generation (sandostatine, lanreotide) et l’apparition d’une insuffisance thyreotrope est rare au cours de ce traitement. Nous rapportons les donnees clinico-bio-radiologiques de cinq patientes (31 a 54 ans) presentant un adenome thyreotrope (TSH = 7,1 ± 7,3 mUI/L, T4L = 36 ± 7,7 pmol/L, T3L = 13,7 ± 3,3 pmol/L ; macro-adenome : n = 4), et ayant developpe une insuffisance thyreotrope isolee au cours du traitement par octreotide (n = 3, 30 mg ou 20 mg/28 jours) ou lanretotide (n = 2, 60 ou 90 mg/28 jours). L’insuffisance thyreotrope apparait precocement apres la premiere (n = 3, 12 a 30 jours), ou la seconde injection (n = 1, 60 jours), avec une diminution de TSH (9,2 ± 8,3 a 0,27 ± 0,23 mUI/L), de T4l (35,8 ± 8,3 a 10,1 ± 1,5 pmol/L) et de T3l (14,1 ± 3,8 a 2,5 ± 0,9 pmol/L). Chez 2 patientes, la surveillance IRM note une diminution du volume adenomateux. La derniere patiente presente un macro-adenome a TSH/GH et l’insuffisance thyreotrope apparait lors d’un traitement prolonge par SMSa lorsque la posologie est augmentee pour controler l’hypersecretion somatotrope (TSH : 5 a 3,8 mUI/L, T4l : 31 a 10,6 pmol/L ; T3l : 13,1 a 3,2 pmol/L). Au total, une insuffisance thyreotrope peut apparaitre au cours du traitement des adenomes thyreotropes par les SMSa. Elle peut etre precoce et etre un facteur predictif de la reponse hormonale et morphologique. Du point de vue therapeutique, elle peut imposer l’adaptation de la posologie des SMSa ou un traitement substitutif par levothyroxine.

Carney complex (CNC) is an autosomal dominant multiple neoplasia, caused mostly by inactivating mutations of the regulatory subunit 1A of the protein kinase A (PRKAR1A). Primary pigmented nodular adrenocortical disease (PPNAD) is the most frequent endocrine manifestation of CNC with a great inter-individual variability. Germline, protein-truncating mutations of phosphodiesterase type 11A (PDE11A) have been described to predispose to a variety of endocrine tumors, including adrenal and testicular tumors.Our objective was to investigate the role of PDE11A as a possible gene modifier of the phenotype in a series of 150 patients with CNC.A higher frequency of PDE11A variants in patients with CNC compared with healthy controls was found (25.3 vs. 6.8%, P0.0001). Among CNC patients, those with PPNAD were significantly more frequently carriers of PDE11A variants compared with patients without PPNAD (30.8 vs. 13%, P = 0.025). Furthermore, men with PPNAD were significantly more frequently carriers of PDE11A sequence variants (40.7%) than women with PPNAD (27.3%) (P0.001). A higher frequency of PDE11A sequence variants was also found in patients with large-cell calcifying Sertoli cell tumors (LCCSCT) compared with those without LCCSCT (50 vs. 10%, P = 0.0056). PDE11A variants were significantly associated with the copresence of PPNAD and LCCSCT in men: 81 vs. 20%, P0.004). The simultaneous inactivation of PRKAR1A and PDE11A by small inhibitory RNA led to an increase in cAMP-regulatory element-mediated transcriptional activity under basal conditions and after stimulation by forskolin.We demonstrate, in a large cohort of CNC patients, a high frequency of PDE11A variants, suggesting that PDE11A is a genetic modifying factor for the development of testicular and adrenal tumors in patients with germline PRKAR1A mutation.

La chirurgie permet dans plus de 95 % des cas d’obtenir une guerison de l’hyperparathyroidie primaire. Dans le cas contraire ou en cas de recidive, la prise en charge necessite une approche methodique. La premiere etape est de s’assurer de la recidive d’un point de vue biologique. L’absence de guerison apres l’exerese d’une glande parathyroidienne pathologique (adenome ou hyperplasie) est en faveur d’une maladie pluri-glandulaire, ce qui conduit a evoquer la possibilite d’une susceptibilite genetique, en raison de l’impact sur l’indication (mutation du recepteur du calcium…) ou la strategie de reprise chirurgicale. Si l’indication operatoire reste formelle (retentissement, severite…), l’enjeu sera alors de determiner avec la plus grande confiance la localisation du tissu parathyroidien pathologique pour optimiser les chances de guerison. Parmi les examens a visee topographique, l’echographie cervicale realisee par un operateur expert, couplee a la scintigraphie au MIBI (avec des tomographies et de l’imagerie de fusion), restent des examens pratiques dans cette indication, mais actuellement concurrencer par le developpement de la prometteuse scintigraphie TEP a la choline. L’imagerie en coupes par scanner ou resonnance magnetique gardent des indications en complement de la scintigraphie, notamment pour les localisations ectopiques. Les progres actuels et a venir de la scintigraphie vont peut-etre conferer une place encore plus limitee a l’exploration par catheterisme pour realiser des dosages etages de PTH. Dans les situations ou la chirurgie ne peut etre envisagee par absence d’imagerie concluante ou en cas d’echec d’une reprise chirurgicale, un traitement medicamenteux par calcimimetique est la strategie a envisager.

Les lesions corticosurrenaliennes benignes regroupent un large eventail de maladies avec des morphologies ainsi que des secretions de steroides distinctes. Contrairement au corticosurrenalome, aucune vision globale moleculaire des alterations moleculaires n’est disponible pour ces tumeurs. Objectifs Fournir une classification moleculaire des tumeurs corticosurrenaliennes benignes, en utilisant une serie de mesures non biaisees pan-genomiques dans une cohorte incluant tous les types de tumeurs corticosurrenaliennes benignes. Methodes L’etude effectuee rapporte l’analyse pan-genomique incluant transcriptome, miRNome, methylome, mutations et alterations chromosomiques de 146 lesions adrenocorticales benignes. Resultats Le transcriptome, le methylome, le miRNome et le statut mutationnel convergent en une seule classification avec quatre groupes principaux : (i) les tumeurs productrices de cortisol, regroupant differents types partageant une activation commune de la voie AMPc/PKA par des mecanismes distincts. Le transcriptome a permis d’identifier une signature steroidogene ; (ii) des adenomes corticosurrenaliens (ACA) sans ou avec une secretion legere de cortisol, associes a des mutations de la beta-catenine ; (iii) des hyperplasies macronodulaires primaires avec des mutations ARMC5, montrant une signature d’expression ovarienne ; (iv) des ACA produisant de l’aldosterone, en dehors d’autres tumeurs benignes. Les alterations epigenetiques et la steroidogenese semblent associees, incluant l’hypomethylation des ilots CpG dans les tumeurs sans ou avec une secretion legere de cortisol, les profils des miARN definissant des groupes moleculaires specifiques, et la regulation directe de l’expression des enzymes steroidogenes par la methylation. Conclusion Cette premiere caracterisation pan-genomique a grande echelle des lesions corticosurrenaliennes benignes represente une nouvelle ressource importante pour l’etude de la tumorigenese corticosurrenalienne et de la steroidogenese.