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International audience; Cushing's syndrome is defined by prolonged exposure to glucocorticoids, leading to excess morbidity and mortality. Diagnosis of this rare pathology is difficult due to the low specificity of the clinical signs, the variable severity of the clinical presentation, and the difficulties of interpretation associated with the diagnostic methods. The present consensus paper by 38 experts of the French Society of Endocrinology and the French Society of Pediatric Endocrinology and Diabetology aimed firstly to detail the circumstances suggesting diagnosis and the biologic diagnosis tools and their interpretation for positive diagnosis and for etiologic diagnosis according to ACTH-independent and -dependent mechanisms. Secondly, situations making diagnosis complex (pregnancy, intense hypercortisolism, fluctuating Cushing's syndrome, pediatric forms and genetically determined forms) were detailed. Lastly, methods of surveillance and diagnosis of recurrence were dealt with in the final section.

International audience; PURPOSE: This study aimed to investigate the genetic cause of food-dependent Cushing syndrome (FDCS) observed in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) and adrenal ectopic expression of the glucose-dependent insulinotropic polypeptide receptor. Germline ARMC5 alterations have been reported in about 25% of PBMAH index cases but are absent in patients with FDCS. METHODS: A multiomics analysis of PBMAH tissues from 36 patients treated by adrenalectomy was performed (RNA sequencing, single-nucleotide variant array, methylome, miRNome, exome sequencing). RESULTS: The integrative analysis revealed 3 molecular groups with different clinical features, namely G1, comprising 16 patients with ARMC5 inactivating variants; G2, comprising 6 patients with FDCS with glucose-dependent insulinotropic polypeptide receptor ectopic expression; and G3, comprising 14 patients with a less severe phenotype. Exome sequencing revealed germline truncating variants of KDM1A in 5 G2 patients, constantly associated with a somatic loss of the KDM1A wild-type allele on 1p, leading to a loss of KDM1A expression both at messenger RNA and protein levels (P = 1.2 × 10(-12) and P < .01, respectively). Subsequently, KDM1A pathogenic variants were identified in 4 of 4 additional index cases with FDCS. CONCLUSION: KDM1A inactivation explains about 90% of FDCS PBMAH. Genetic screening for ARMC5 and KDM1A can now be offered for most PBMAH operated patients and their families, opening the way to earlier diagnosis and improved management.

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.

Genetic variants in components of the protein kinase A (PKA) enzyme have been associated with various defects and neoplasms in the context of Carney complex (CNC) and in isolated cases, such as in primary pigmented nodular adrenocortical disease (PPNAD), cortisol-producing adrenal adenomas (CPAs), and various cancers. PRKAR1A mutations have been found in subjects with impaired cAMP-dependent signaling and skeletal defects; bone tumors also develop in both humans and mice with PKA abnormalities. We studied the PRKACB gene in 148 subjects with PPNAD and related disorders, who did not have other PKA-related defects and identified two subjects with possibly pathogenic PRKACB gene variants and unusual bone and endocrine phenotypes. The first presented with bone and other abnormalities and carried a de novo c.858_860GAA (p.K286del) variant. The second subject carried the c.899C>T (p.T300M or p.T347M in another isoform) variant and had a PPNAD-like phenotype. Both variants are highly conserved in the PRKACB gene. In functional studies, the p.K286del variant affected PRKACB protein stability and led to increased PKA signaling. The p.T300M variant did not affect protein stability or response to cAMP and its pathogenicity remains uncertain. We conclude that PRKACB germline variants are uncommon but may be associated with phenotypes that resemble those of other PKA-related defects. However, detailed investigation of each variant is needed as PRKACB appears to be only rarely affected in these conditions, and variants such as p.T300M maybe proven to be clinically insignificant, whereas others (such as p.K286del) are clearly pathogenic and may be responsible for a novel syndrome, associated with endocrine and skeletal abnormalities.

Objective We previously described a family in which predisposition to pheochromocytoma (PCC) segregates with a germline heterozygous KIF1B nucleotide variant (c.4442G>A, p.Ser1481Asn) in three generations. During the clinical follow-up, one proband’s brother, negative for the KIF1B nucleotide variant, developed a bilateral PCC at 31 years. This prompted us to reconsider the genetic analysis. Design and methods Germline DNA was analyzed by next-generation sequencing (NGS) using a multi-gene panel plus MLPA or by whole exome sequencing (WES). Tumor-derived DNA was analyzed by SnapShot, Sanger sequencing or NGS to identify loss-of-heterozygosity (LOH) or additional somatic mutations. Results A germline heterozygous variant of unknown significance in MAX (c.145T>C, p.Ser49Pro) was identified in the proband’s brother. Loss of the wild-type MAX allele occurred in his PCCs thus demonstrating that this variant was responsible for the bilateral PCC in this patient. The proband and her affected grandfather also carried the MAX variant but no second hit could be found at the somatic level. No other pathogenic mutations were detected in 36 genes predisposing to familial PCC/PGL or familial cancers by WES of the proband germline. Germline variants detected in other genes, TFAP2E and TMEM214, may contribute to the multiple tumors of the proband. Conclusion In this family, the heritability of PCC is linked to the MAX germline variant and not to the KIF1B germline variant which, however, may have contributed to the occurrence of neuroblastoma (NB) in the proband.

Resume Il est commun d’etablir le diagnostic des dysfonctions thyroidiennes sur des modifications de la thyrostimuline hypophysaire (TSH), et de les quantifier par le degre d’abaissement ou d’augmentation des concentrations de T4 et de T3 circulantes. Cette conception est mise en defaut lorsque des facteurs genetiques, voire pharmacologiques, determinent des alterations de la sensibilite tissulaire a l’action des iodothyronines. La situation la moins rare est celle d’etats de secretion inappropriee de TSH, responsables d’hyperhormonemie thyroidienne familiale sans que ne s’expriment clairement de manifestations thyrotoxiques, en raison de la resistance des recepteurs beta des iodothyronines. Les mutations du recepteur alpha sont responsables de severes modifications du morphotype osseux et du comportement, alors que les concentrations de T4 et T3 et de TSH sont pratiquement normales, mais comportent une subtile majoration du rapport T3/T4. Le transporteur MCT8 est implique dans la penetration de la T3 dans les structures fines neuronales ; des mutations de MCT8 ont permis de comprendre les etats de deficience intellectuelle severe lies a l’X correspondant a l’entite traditionnelle du syndrome d’Allan-Herndon-Dudley. D’autres situations resultant d’un defaut d’activation de T4 en T3, se revelent par des retards de croissance et du developpement intellectuel, des atteintes myopathiques, un deficit immunitaire, une azoospermie. Il existe aussi des etats d’hypersensibilite aux hormones thyroidiennes. Il faut apprendre a reconnaitre ces situations dont la presentation clinique et/ou hormonale n’evoque a priori nullement un desordre thyroidien. Il apparait qu’elles ont des correspondances pharmacologiques et environnementales, notamment avec l’amiodarone, la dronedarone et certains perturbateurs endocriniens. Les pathologies liees aux modifications de la sensibilite hormonale elargissent considerablement le champ traditionnel de l’endocrinologie.

Background: Thermal ablation is a minimally invasive technique that is gradually acknowledged as an effective alternative to surgery to treat thyroid nodules. Two main techniques have been described: radiofrequency (RFA) and laser ablation. Objective: To evaluate the safety and efficacy of the two main techniques (RFA and laser ablation) for the treatment of benign thyroid nodules. Patients: This bicentric retrospective study included 166 consecutive patients, who received clinical, biological and ultrasound evaluations for thyroid nodules, from October 2013 to November 2017. Methods: One of the two techniques was proposed if a nodule was proven to be benign after fine needle aspiration cytology or micro-biopsy. Adverse events and outcomes (symptoms, nodule reduction) were assessed at 6 weeks and 6, 12, and 18 months after treatment. Results: One hundred and eighty-nine nodules (mean size 17.5 ± 16.9 mL, 86.1% palpable) were treated by RFA (n = 108 (57.1%)) or laser ablation (n = 81 (42.9%)) in 166 patients (80.1% women, mean age 51.7 years). Two cases of transient recurrent laryngeal nerve palsy, one hematoma, and two successfully drained abscesses (5/166 = 3%) were observed. Clinical symptoms improved significantly in the two groups (anterior cervical discomfort –83.6%, esthetic complaints –84.9% and dysphagia –86.4%). Nodule volume (mL) decreased significantly (baseline vs. 18 months) from 20.4 ± 18.6 to 5.8 ± 6.6 (−75%) in the RFA, and from 13.6 ± 13.3 to 3.4 ± 4.1 (−83.9%) in the laser ablation groups. Conclusions: Transient but potentially serious adverse events were reported in 3% of patients. A significant volumetric reduction was achieved with both techniques, regardless of nodule’s characteristics, at 18 months.

Purpose: To investigate the genetic cause of Food-dependent Cushing’s syndrome (FDCS) observed in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) and adrenal ectopic expression of the GIP receptor (GIPR). Germline ARMC5 alterations have been reported in about 25 % of PBMAH index cases but are absent in patients with FDCS. Methods: A multi-omics analysis of PBMAH tissues from 36 patients treated by adrenalectomy was performed (RNAseq, SNP array, methylome, miRNome, exome sequencing). Results: The integrative analysis revealed three molecular groups with different clinical features: G1, PBMAH due to ARMC5 inactivating variants; G2, with GIPR ectopic expression and FDCS; and G3, with a less severe phenotype. Exome sequencing revealed germline truncating variants of LSD1/KDM1A in the G2 group, constantly associated with a somatic loss of the LSD1/KDM1A wildtype allele on 1p, leading to a loss of LSD1/KDM1A expression both at mRNA and protein levels (p=1.2x10-12 and p

Usual clinical presentation of secreting pheochromocytoma is headache, palpitations, sweating and paroxysmal hypertension but emergency situations are also described. We herein reported a case of pheochromocytoma revealed by cardiogenic shock on dilated cardiomyopathy with improvement of left ventricular ejection fraction (LVEF) after the introduction of an inhibitor of tyrosine hydroxylase. A 41-year-old patient was admitted in the ICU for cardiogenic shock with initially hypertension emergency and tachycardia. Transthoracic echocardiography revealed a dilated cardiomyopathy with estimated 2-dimensional LVEF at 15 %. A computed tomography angiography was performed to rule out a pulmonary embolism and led to discover bilateral adrenal tumors measured at 3 cm and 2 cm respectively on the left and right sides. Plasmatic noradrenaline was increased 5.5 μg/L (N C, p.S49P). Congestive heart failure has a poor prognosis unless a correctable cause is identified. For the treatment of pheochromocytoma, surgical removal of tumor is the first choice but in particular cases, using an inhibitor of tyrosine hydroxylase could be a short-term alternative in preparation to surgery.

Growth hormone (GH) deficiency (GHD) is the most common late endocrine complication in childhood cancer survivors (CCS). We here review the etiologies, consequences, biological assessment, and treatment of GHD in adult CCS. In summary, screening of GHD should be proposed for every patient treated by cranial irradiation and surgery of the pituitary-hypothalamic area. Since chemotherapy and any brain tumor surgery may lead to GHD, this recommendation might be extended to every CCS. GHD contributes to the alteration of quality of life (QOL) and health status observed in CCS. GH therapy improves metabolic profile, bone mineralization, muscular performance, and QOL in adult GHD. Meta-analysis and pharmaceutical companies’ prospective databases of adult GH replacement are reassuring about the risk of second malignancies and recurrence. Reimbursement of GH therapy is currently restrained in most countries to patients with severe GHD (GH

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.

Context Oral once-daily dual-release hydrocortisone (DR-HC) replacement therapy has demonstrated an improved metabolic profile compared to conventional 3-times-daily (TID-HC) therapy among patients with primary adrenal insufficiency. This effect might be related to a more physiological cortisol profile, but also to a modified pattern of cortisol metabolism. Objective This work aimed to study cortisol metabolism during DR-HC and TID-HC. Design A randomized, 12-week, crossover study was conducted. Intervention and Participants DC-HC and same daily dose of TID-HC were administered to patients with primary adrenal insufficiency (n = 50) vs healthy individuals (n = 124) as controls. Main Outcome Measures Urinary corticosteroid metabolites were measured by gas chromatography/mass spectrometry at 24-hour urinary collections. Results Total cortisol metabolites decreased during DR-HC compared to TID-HC (P

Objective: The Carney Complex (CNC) is a multiple endocrine and non endocrine neoplasia, mostly due to PRKAR1A mutations. The PRKAR1A mutation c.709(-7-2)del located in the intron 7 is one of the three known hot spot. The objective of this study is to described the CNC manifestations presented by patients harboring the c.709(-7-2)del. Methods: This study is a multicenter retrospective longitudinal study. Patients data have been collected from medical files. Multicenter retrospective study. Age at the diagnosis or at the screening of the different CNC manifestations is described by mean +/- standard deviation or median (interquartile) according to the distribution. Results: 41 patients [14 index cases and 37 relatives, 29 females, 43.6 ±14.3 years old (yo)] from 15 families have been included. 58% of the cohort including the 14 index cases presented with a primary pigmented adrenal disease (PPNAD) at 24-yo (18-40). For the remaining 17 patients, only 3 patients had normal glucocorticoid biological evaluation while others presented with subclinical hypercortisolism diagnosed at 35-yo (22-50). 7% of the cohort had an abnormal IGF1 and/or GH after oral glucose tolerance test while other patients had normal evaluation with a last test performed at 41 ±15yo. 22% of patients presented with lentigines diagnosed at 43yo (24-51) while others had no dermatological lesions at the last examination performed at 37 ±14yo. 13% of patients had thyroid nodules or papillary carcinoma diagnosed at 46 ±15yo (normal ultrasound for others at 37 ±15yo). At the last cardiac ultrasound, pituitary magnetic resonance imaging (MRI), spine MRI, testicular ultrasound, mammography performed at 40±15yo, 37.9±14.3yo, 46±12yo, 35±13yo and 48±12yo, no patient had cardiac myxoma, pituitary adenoma, schwannoma, testicular calcifying tumor or breast myxoma. Overall, 52% of the relatives did not have any manifestations of the disease. Penetrance of the disease is 65%. Conclusion: The phenotype of patients carrying the c.709(-7-2)del PRKAR1A mutation is restricted to PPNAD, lentigines, fluctuating somatotroph anomalies and thyroid tumors. Follow-up of these patients should also be individualized from other CNC patients. Imaging, especially repeated cardiac ultrasound may not be needed to follow these patients The results of this real life study will be useful to elaborate further recommendation for follow-up of CNC patients.

Background: Lipomatosis is a condition in which multiple lipomas are present on the body. Different entities which are accompanied by multiple lipomas include Proteus syndrome, Cowden syndrome and related disorders due to PTEN gene mutations, MEN1, benign symmetric lipomatosis (Madelung or Launois-Bensaude disease), Dercum’s Disease, familial lipodystrophy, hibernomas, epidural lipomatosis, familial angiolipomatosis, and meso-somatous lipomatosis (LMS) still called Roch-Leri lipomatosis. LMS is characterized by the presence of many discrete, encapsulated lipomas of 2 to 5 cm, painless, at the level of the trunk and forearms. The aim of the present study was to determine the clinico-biological phenotype of LMS, as compared to controls. Patients and methods: In this single-center study (NCT01784289), 18 healthy controls (C) and 11 LMS were included after examining the cohort of 76 patients referred for suspected lipodystrophic syndrome between 2009 and 2019 in the Endocrinology Department of a University Hospital. Clinical (sex, age, weight, BMI, blood pressure (BP), alcohol consumption), metabolic (fasting blood glucose (FBG) and insulin levels, lipid balance, ASAT, ALAT, GammaGT, leptin), immuno-inflammatory (CBC, lymphocyte immunophenotyping), and anthropometric (% of body fat in DEXA, steatosis and intra-abdominal / total abdominal fat ratio (IAF / TAF) in MRI) were evaluated. Results: The following parameters, expressed as % or median, differed significantly between LMS vs. C groups, respectively: weight 100 vs. 69kg (p 5 in 82% of LMS patients and lipomas were localized first to the forearms (82%), then the thighs (73%) and the abdomen (55%). At diagnosis, the age of LMS patients was 20 years old; 55% of the LMS patients had a BMI above 30 and 45% above 25. No patient had excessive alcohol consumption. Five had a history of auto-immuneor inflammatory disease: 1 hyperthyroidism, 1 hypothyroidism, 1 multiple sclerosis, 1 vitiligo, 1 Raynaud syndrome. Conclusion: LMS mainly affects overweight men and is associated with hypertension, hyperinsulinism, increased gammaGT and a decrease in CD3, CD4 and CD8 lymphocytes, suggesting an immune dysregulation, all the more so that 45% had an associated auto-immune/inflammatory disease.

The names of the working groups that collaborated in the study reported in this article were inadvertently omitted from the byline. The corrected byline should … 2019;42

Natriuretic peptides are a group of hormones including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C type (CNP), urodilatin and guanilyn. ANP (half-life: 2-4 min), is secreted by the atrium, BNP (half-life: 20 min) by the ventricle, CNP by the vascular endothelium, urodilatin by the kidney and guanylin by the intestine. These natriuretic peptides prevent water and salt retention through renal action, vasodilatation and hormonal inhibition of aldosterone, vasopressin and cortisol. These peptides also have a recently demonstrated metabolic effect through an increase of lipolysis, thermogenesis, beta cell proliferation and muscular sensitivity to insulin. Blood levels of these natriuretic peptides depend on "active NPR-A receptors/clearance NPR-C receptors", the last ones being abundant on adipocytes. Therefore, natriuretic peptides act as adipose tissue regulator and constitute a link between blood pressure and metabolic syndrome. They are used as markers and treatment of cardiac failure. Other applications are on going. BNP and NT-proBNP (inactive portion de la pro-hormone) are used as markers of cardiac failure since they have a longer half-life than ANP. BNP decrease is quicker and more important than that one of NT-ProBNP in case of improvement of cardiac failure. Chronic renal insufficiency and beta-blockers increase BNP levels. BNP measurement is useless under treatment with neprilysine inhibitors such as sacubitril, one of the neutral endopeptidases involved in catabolism of natriuretic peptides. The association sacubitril/valsartan is a new treatment of chronic cardiac failure, acting through the decrease of ANP catabolism.

Les hyperthyroidies liees a l’amiodarone ont un pronostic cardiovasculaire grave majorant le risque de mortalite de 30 a 50 % [1] . La thyroidectomie est proposee par l’ETA comme une procedure de sauvetage chez les patients ayant une deterioration de la fonction cardiaque liee a une cardiopathie severe ou une arythmie maligne [2] . Son benefice est prouve chez les patients a FEVG alteree reduisant la mortalite a 10 ans en comparaison avec le traitement medical. Une recuperation cardiaque est decrite avec le retablissement de l’euthyroidie [3] . Nous detaillons ici les modalites de prise en charge perioperatoire de 3 patients thyroidectomises en urgence. Chez les 3 patients, les thyroidectomies ont ete realisees en phase d’hyperthyroidie. Tous presentaient une cardiopathie severe avec une fonction systolique alteree (FEVG ≤ a 40 %) rendant la situation cardiologique instable. Deux patients ont presente une hyperthyroidie de type 1 sur goitre multinodulaire. Le delai entre le diagnostic d’hyperthyroidie et l’introduction d’antithyroidiens de synthese etait de 3 mois. La thyroidectomie a eu lieu 5 et 6 mois apres le debut de l’hyperthyroidie. Le troisieme patient presentait une hyperthyroidie de type 2 traitee par corticotherapie des le diagnostic. La thyroidectomie a ete realisee apres 3 mois de traitement medical. Des seances de plasmapherese ont ete necessaires en preoperatoire. Les suites operatoires ont ete simples. Aucune recuperation de la fonction cardiaque n’etait observee en post operatoire malgre l’euthyroidie. Les deux patients avec hyperthyroidie de type 1 ont beneficie d’une transplantation cardiaque. En resume, malgre une chirurgie a risque, la thyroidectomie n’a pas engendre de complication immediate au decours. En revanche, nous n’avons pas observe d’amelioration cardiaque, peut-etre en raison du retard a l’instauration du traitement medical dans les hyperthyroidies de type 1 et/ou en raison du caractere trop tardif de la thyroidectomie. L’instabilite cardiaque doit donc pousser a une prise en charge rapide de l’hyperthyroidie.

Summary PBMAH is a rare etiology of Cushing syndrome (CS). Familial clustering suggested a genetic cause that was recently confirmed, after identification of inactivating germline mutations in armadillo repeat-containing 5 (ARMC5) gene. A 70-year-old female patient was admitted due to left femoral neck fracture in May 2014, in Orthopedics Department. During hospitalization, hypertension (HTA) and hypokalemia were diagnosed. She presented with clinical signs of hypercortisolism and was transferred to the Endocrinology ward for suspected CS. Laboratory workup revealed: ACTH Learning points: PBMAH is a rare etiology of CS, characterized by functioning adrenal macronodules and variable cortisol secretion. The asymmetric/asynchronous involvement of only one adrenal gland can also occur, making disease diagnosis a challenge. Familial clustering suggests a genetic cause that was recently confirmed, after identification of inactivating germline mutations in armadillo repeat-containing 5 (ARMC5) gene. The insidious nature of this disease and the well-known deleterious effect of hypercortisolism favor genetic study of other family members, to diagnose and treat these patients timely. As ARMC5 is expressed in many organs and recent findings suggest an association of PBMAH and meningioma, a watchful follow-up is required.

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.

The purpose of this study was to analyse the characteristics of 6 patients managed in a university hospital between 1996 and 2016 for non-islet cell tumor hypoglycemia (NICTH), a form of hypoglycaemia due to the paraneoplastic secretion of IGF-2 or its related substances. RESULTS: Three of these 6 patients (50%), aged over 69 years, including 2 with acromegaloid phenotype, presented with a pleural solitary fibrous tumor (SFT), with median diameter 20 cm (interquartile range, 12.5-20.5) with a low median SUV (3.3 g/mL (QR, 2-7.5)) on 18F-FDG PET. The other 3 patients presented respectively neuroendocrine carcinoma (NEC) of the palate (70-year-old woman), retroperitoneal myxofibrosarcoma (66-year-old man) and meningeal hemangiopericytoma (36-year-old woman). All 3 were inoperable and did not respond to any therapy other than glucose solution. Corticosteroid therapy was effective in the 3 SFTs and the NEC. One of the SFTs recurred 10 years later with asymptomatic hypoglycemia, which resolved after reintervention. Median (IQR) blood glucose levels of the 6 patients was 0.4g/L (QR, 0.31-0.41), with hypoinsulinemia at 0.7mIU/L (QR 0.7-2.0), undetectable GH, low IGF-1, normal IGF-2 level in 5/6 cases, a high IGF-2:IGF-1 ratio at 26.9 (QR, 20.8-37.8), hypokalemia and hypomagnesemia. CONCLUSION: NICTH is a rare syndrome, which should be considered in the presence of hypoinsulinemic hypoglycemia with low GH and IGF-1, and a IGF-2:IGF-1 ratio>10. Corticosteroid therapy was effective in elderly subjects, particularly with solitary fibrous tumor, which was generally operable. Hemangiopericytoma and myxofibrosarcoma had poor prognosis in younger patients.

OBJECTIVE The long-term outcome of allogenic islet transplantation is unknown. The aim of this study was to evaluate the 10-year outcome of islet transplantation in patients with type 1 diabetes and hypoglycemia unawareness and/or a functioning kidney graft. RESEARCH DESIGN AND METHODS We enrolled in this prospective parallel-arm cohort study 28 subjects with type 1 diabetes who received islet transplantation either alone (ITA) or after a kidney graft (IAK). Islet transplantation consisted of two or three intraportal infusions of allogenic islets administered within (median [interquartile range]) 68 days (43–92). Immunosuppression was induced with interleukin-2 receptor antibodies and maintained with sirolimus and tacrolimus. The primary outcome was insulin independence with A1C ≤6.5% (48 mmol/mol). Secondary outcomes were patient and graft survival, severe hypoglycemic events (SHEs), metabolic control, and renal function. RESULTS The primary outcome was met by (Kaplan-Meier estimates [95% CI]) 39% (22–57) and 28% (13–45) of patients 5 and 10 years after islet transplantation, respectively. Graft function persisted in 82% (62–92) and 78% (57–89) of case subjects after 5 and 10 years, respectively, and was associated with improved glucose control, reduced need for exogenous insulin, and a marked decrease of SHEs. ITA and IAK had similar outcomes. Primary graft function, evaluated 1 month after the last islet infusion, was significantly associated with the duration of graft function and insulin independence. CONCLUSIONS Islet transplantation with the Edmonton protocol can provide 10-year markedly improved metabolic control without SHEs in three-quarters of patients with type 1 diabetes, kidney transplanted or not.

Introduction Le spectre clinique de l’hyperplasie macronodulaire bilaterale primitive des surrenales (HMBPS) est large. La secretion de cortisol peut etre mediee par des recepteurs illegitimes a l’ACTH dont le GIP-R, responsable de syndromes de Cushing dependants de l’alimentation. Des mutations germinales inactivatrices d’ARMC5 sont identifiees dans 20 % des cas. Objectif Caracteriser les alterations moleculaires dans les HMBS. Methodes Extractions des acides des tissus d’HMBS congeles de 36 patients surrenalectomises (oncotheque COMETE) ; 15/36 patients mutes pour ARMC5. Analyse des alterations du nombre de copie (Illumina HumanCore BeadChips, 306.702 SNPs). Etude dy profil de methylation tumoral (Illumina MethylationEPIC BeadChip array, 866.895 sondes). Sequencage Illumina des ARN et miARN (Genomic, Institut Cochin). Resultats Pas d’alteration chromosomique dans la moitie des echantillons. Perte d’heterozygtie sans alteration du nombre de copie en 16p observee chez 6 patients mutes ARMC5. Ont aussi ete mis en evidence : gain en 1q (n = 5) ; gain en 9q21.11–9q34.3 (n = 3, locus SF1). L’etude des 5000 positions les plus differentiellement methylees a permis d’etablir 2 groupes correspondant au statut ARMC5. Un profil micro ARN specifique a ete observe pour les tumeurs ARMC5 mutes. L’analyse du transcriptome differencie les tumeurs ARMC5 mutees des autres. Parmi les tumeurs ARMC5 sauvage, un sous-groupe se distingue par la surexpression du GIPR (fold change 5.8, p = 5.7E–09). Conclusion Cette premiere analyse de genomique integree dans l’HMBPS reflete l’heterogeneite clinique au niveau moleculaire. Elle distingue 3 groupes dont l’un est conduit par la mutation ARMC5,un autre caracterise par la surexpression du GIPR. Le troisieme doit etre etudie.

Introduction L’HMBS est une pathologie rare et heterogene, caracterisee par de multiples macronodules surrenaliens, responsables d’un hypercortisolisme d’intensite variable. La moitie des patients avec forme severe, traites par surrenalectomie bilaterale, presente une mutation germinale inactivatrice heterozygote du gene suppresseur de tumeurs ARMC5, et 80 % pour les formes clairement familiales, contre seulement 20 % des formes sporadiques. L’objectif de cette etude etait d’etablir des criteres predictifs de mutation d’ARMC5. Methodes 454 cas index francais et europeens porteurs d’HMBS ont ete genotypes pour ARMC5 a Cochin. Parmi ces 454 patients, nous avons analyse retrospectivement les donnees cliniques, radiologiques et biologiques de 264 patients suivis dans cinq services d’endocrinologie universitaires francais (reseau COMETE). Resultats 40 cas index sur les 264 analyses (15,2 %) presentent une mutation germinale inactivatrice d’ARMC5, coherent avec le taux de mutation observe dans la cohorte de 454 patients (14,3 %). Les patients mutes ont une pathologie plus severe que les patients non-mutes, en termes d’intensite de l’hypercortisolisme biologique, de morphologie surrenalienne et de complications. 100 % des patients mutes presentent des nodules surrenaliens bilateraux ET un cortisol plasmatique apres freinage minute a la dexamethasone superieur a 50 nmol/L, alors que seulement 61,6 % des patients non-mutes ont l’association de ces deux criteres. Du fait de sa valeur predictive negative de 100 %, l’absence de cette association permet d’exclure une mutation d’ARMC5. Conclusion Restreindre l’indication du sequencage d’ARMC5 aux patients presentant des nodules surrenaliens bilateraux et une secretion autonome de cortisol permettrait d’eviter un genotypage negatif chez un tiers des patients sans perte de sensibilite.

Introduction Le complexe de Carney (CNC) est un syndrome regroupant des neoplasies endocriniennes et non endocriniennes. Cette etude decrivant les caracteristiques des lesions mammaires des patientes avec CNC, les autres manifestations du CNC et le genotype PRKAR1A, s’est particulierement interessee aux carcinomes mammaires, cancer le plus frequent chez la femme et principale cause de deces par cancer dans le monde. Methodes Cette cohorte de 70 patients avec CNC provient d’un suivi prospectif multicentrique francais de 3 ans (Espiard et al. JCEM 2020). L’analyse des 50 femmes incluses a porte sur les manifestations de CNC (lesions mammaires particulierement), le genotype et les caracteristiques hormonales. Resultats Parmi les 38 femmes avec imagerie mammaire, dix presentaient des lesions benignes et six des carcinomes : un carcinome in-situ a 54 ans et cinq cancers invasif avant 50 ans et une recurrence controlaterale. La survenue du cancer mammaire chez les patientes avec CNC etait plus frequente et l’âge moyen 17 ans plus precoce (44,7 ans) que la population generale. Tous les cancers mammaires sont survenus chez des patientes mutees PRKAR1A, avec de bons facteurs pronostic : recepteurs hormonaux positifs, HER2 negatif, un seul cancer metastatique. Il n’y avait pas d’association entre les carcinomes mammaires et les manifestations du CNC ou facteurs de risque conventionnels. Discussion Les lesions mammaires sont frequentes chez les femmes atteintes de CNC. Le carcinome mammaire pourrait etre une « nouvelle » manifestation de cette maladie, une strategie de depistage et un suivi adequat pourraient etre proposes.

Background Myotonic dystrophy (DM1), a neuromuscular disease related to DMPK gene mutations, is associated to endocrine disorders and cancer. A routine endocrine work-up, including thyroid ultrasound (US), was conducted in 115 genetically-proven DM1 patients in a neuromuscular reference center. The aim of this study was to determine the prevalence and the causes of US thyroid abnormalities in DM1. Results In the whole population (age 45.1 ± 12.2 years, 61.7% female), palpable nodules or goiters were present in 29.2%. The percentage of US goiter (thyroid volume > 18 mL) and US nodules were, respectively, 38.3 and 60.9%. Sixteen of the 115 patients had a thyroidectomy, after 22 fine-needle aspiration cytology guided by thyroid imaging reporting and data system (TIRADS) classification. Six micro- (1/6 pT3) and 3 macro-papillary thyroid carcinoma (PTCs) (2/3 intermediate risk) were diagnosed (7.9% of 115). Thyroid US led to the diagnosis of 4 multifocal and 2 unifocal (including 1 macro-PTC) non-palpable PTCs. Ultrasound thyroid volume was positively correlated to body mass index (BMI) (p = 0.015) and parity (p = 0.036), and was inversely correlated to TSH (p

Mutations in the gene encoding the protein kinase A (PKA) catalytic subunit α have been found to be responsible for cortisol-producing adenomas (CPAs). In this study, we identified by whole-exome sequencing the somatic mutation p.S54L in the PRKACB gene, encoding the catalytic subunit β (Cβ) of PKA, in a CPA from a patient with severe Cushing syndrome. Bioluminescence resonance energy transfer and surface plasmon resonance assays revealed that the mutation hampers formation of type I holoenzymes and that these holoenzymes were highly sensitive to cAMP. PKA activity, measured both in cell lysates and with recombinant proteins, based on phosphorylation of a synthetic substrate, was higher under basal conditions for the mutant enzyme compared with the WT, while maximal activity was lower. These data suggest that at baseline the PRKACB p.S54L mutant drove the adenoma cells to higher cAMP signaling activity, probably contributing to their autonomous growth. Although the role of PRKACB in tumorigenesis has been suggested, we demonstrated for the first time to our knowledge that a PRKACB mutation can lead to an adrenal tumor. Moreover, this observation describes another mechanism of PKA pathway activation in CPAs and highlights the particular role of residue Ser54 for the function of PKA.

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 WT index 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.