In-frame seven amino-acid duplication in AIP arose over the last 3000 years, disrupts protein interaction and stability and is associated with gigantism.

Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are associated with pituitary adenoma, acromegaly and gigantism. Identical alleles in unrelated pedigrees could be inherited from a common ancestor or result from recurrent mutation events.EDGE Project ID: 172

Mutations d’AIP (Aryl hydrocarbon receptor-Interacting Protein)dans les adénomes hypophysaires sporadiques

Familial Isolated Pituitary Adenomas (FIPA) have recently been identified as a newfamilial predisposition for pituitary adenomas. The search for a candidate locus has led to thediscovery of germline mutations in AIP (Aryl hydrocarbon receptor-Interacting Protein) gene,which encodes for a co-chaperone protein associated with the transcription factor AhR (Arylhydrocarbon Receptor). AIP gene mutations have also been described in patients with apparentlysporadic pituitary adenomas.The aim of the study was to determine the prevalence of AIP mutations among a cohortof patients with apparently sporadic pituitary adenomas and to report the clinical, hormonal andradiological characteristics of the mutated patients.The entire coding sequence of AIP has been screened for germline mutations in 636patients with a pituitary adenoma and no familial history of pituitary adenomas and who werefollowed at Bicetre Hospital between 2007 and 2012.Twenty-eight of these patients (4,4%) had an AIP germline mutation. AIPmut patientswere younger at diagnosis (28,5 ± 13 vs 42 ± 16,9 ans, P < 0,0001). Somatotroph and lactotrophmacroadenomas were predominant. Mixed GH-PRL secreting adenomas were more frequentamong AIPmut patients (62% versus 19%, P < 0,01). Gigantism was also more frequentlyencountered in AIPmut patients (75% vs 8,6%, P < 0,0001), without any differences in terms ofclinical presentation and treatment modalities.This work confirms the low prevalence of AIP mutations in patients with apparentlysporadic pituitary adenomas. However, AIP gene screening should be considered in youngpatients, especially when they are giants.Les adénomes hypophysaires familiaux isolés (FIPA) sont des formes familialesd’adénomes hypophysaires pour lesquels l’atteinte endocrinienne est limitée à l’hypophyse. Larecherche d’un locus chromosomique associé a abouti à la découverte de mutations du gène AIP(Aryl hydrocarbon receptor-Interacting Protein), codant pour une protéine aux domainesfonctionnels conservés, dont le rôle connu est celui d’une protéine co-chaperonne d’AhR (Arylhydrocarbon Receptor). Des mutations de ce gène ont également été décrites chez des patientsporteurs d’adénomes apparemment sporadiques.L’objectif de ce travail était d’étudier une cohorte de patients porteurs d’adénomesapparemment sporadiques afin de préciser la prévalence des mutations dans cette population etde décrire la présentation clinique, hormonale et morphologique associée à ces variantsnouvellement trouvés.Le séquençage de la région codante d’AIP a été réalisé chez 636 patients qui neprésentent aucun antécédent personnel ni familial évocateur d’une prédisposition génétique etqui ont été suivis dans le Service d’Endocrinologie de l’hôpital Bicêtre entre 2007 et 2012.Vingt-huit de ces patients (4,4%) sont porteurs d’une mutation d’AIP. Les sujets mutéssont plus jeunes au diagnostic (28,5 ± 13 vs 42 ± 16,9 ans, P < 0,0001). Ils présententmajoritairement des macro-adénomes somatotropes et lactotropes, avec des adénomes mixtesGH+PRL plus fréquents que chez les sujets non mutés (62% vs 19%, P < 0,01). Les casd’acromégalogigantisme sont plus nombreux chez les patients mutés (75% vs 8,6%, P < 0,0001)sans différence significative entre les deux groupes en termes de présentation clinique et detraitement.Ce travail confirme la faible prévalence des mutations d’AIP parmi les adénomesapparemment sporadiques. Rechercher une mutation chez un jeune patient est toutefois unestratégie rentable, en particulier si celui-ci présente un acromégalogigantisme

Role of AIP (Aryl Hydrocarbon Receptor Interacting Protein) in Pituitary Adenoma Tumorigenesis

Nous avons souhaité, dans ce travail de Thèse, préciser l'impact de l'invalidation d'AIP sur la fonction sécrétoire et la prolifération des cellules somatotropes in vivo et explorer in vitro les voies de signalisation potentiellement impliquées dans la tumorigenèse hypophysaire AIP-dépendante. L'analyse du phénotype des souris Aip+/-, en particulier de la sécrétion pulsatile de GH, montre que, contrairement à l'Homme, les animaux mutés ne développent pas de gigantisme ni d'hypersécrétion de GH et que la pénétrance de la pathologie tumorale hypophysaire est beaucoup plus faible qu'initialement décrit. Les études réalisées sur les fibroblastes de patients mutés pour AIP et porteurs d'un adénome hypophysaire ainsi que sur les cellules somatolactotropes de rat GH3 révèlent que les mutations d'AIP altèrent l'activité transcriptionnelle d'AhR (Aryl hydrocarbon Receptor), mais affectent également la voie de signalisation de l'AMPc. Enfin, des mutations germinales du gène GPR101, récemment identifiées dans des cas d'acromégalie sporadique, ont aussi été trouvées chez des patients porteurs d'un adénome hypophysaire sporadique non somatotrope, sans association avec les mutations d'AIP. Ce travail a ainsi permis de préciser les conséquences des mutations d'AIP sur la fonction somatotrope et la signalisation d'AhR. Le rôle de l'AMPc dans la tumorigenèse hypophysaire AIP-dépendante sera évalué dans un nouveau modèle de souris transgénique.In this work, we investigated the effects of AIP deficiency in vivo on somatotroph cells, both at the secretory and proliferative levels and explored in vitro the signaling pathways potentially involved in AIP-dependent pituitary tumorigenesis. Phenotype analyzes of Aip+/- mice, especially of GH pulsatility, show that, unlike humans, mutant mice do not develop gigantism nor GH hypersecretion and present with a much lower penetrance of pituitary adenomas than initially described. In vitro studies in fibroblasts of AIP-mutation positive patients with pituitary adenomas and in somatolactotroph GH3 cells demonstrate that AIP mutations alter AhR (Aryl hydrocarbon Receptor) transcriptional activity and modify the cAMP pathway. Finally, GPR101 mutations, recently reported in patients with sporadic acromegaly, have also been identified in a small portion of patients with sporadic non-somatotroph pituitary adenomas, without any association with AIP mutations. This research work defines the consequences of AIP mutations on somatotroph cell function and AhR transcriptional activity. The role of cAMP signaling in AIP-related pituitary tumorigenesis will be further evaluated in a new transgenic mouse model

Management of X-linked hypophosphatemia in adults

International audienceX-linked hypophosphatemia (XLH) is caused by mutations in the PHEX gene which result in Fibroblast Growth Factor-23 (FG-F23) excess and phosphate wasting. Clinically, XLH children present with rickets, bone deformities and short stature. In adulthood, patients may still be symptomatic with bone and joint pain, osteomalacia-related fractures or pseudofractures, precocious osteoarthrosis, enthesopathy, muscle weakness and severe dental anomalies. Besides these musculoskeletal and dental manifestations, adult XLH patients are also prone to secondary and tertiary hyperparathyroidism, cardiovascular and metabolic disorders. Pathophysiology of hyperparathyroidism is only partially understood but FGF23 excess and deficient production of calcitriol likely contributes to its development. Similarly, the pathophysiological mechanisms of potential cardiovascular and metabolic involvements are not clear, but FGF-23 excess may play an essential role. Treatment should be considered in symptomatic patients, patients undergoing orthopedic or dental surgery and women during pregnancy and lactation. Treatment with oral phosphate salts and active vitamin D analogs has incomplete efficacy and potential risks. Burosumab, a recombinant human monoclonal antibody against FGF-23, has proven its efficacy in phase 2 and phase 3 clinical trials in adult patients with XLH, but currently its position as first line or second line treatment differ among the countries

[11^{11}C]glyburide PET imaging for quantitative determination of the importance of Organic Anion-Transporting Polypeptide transporter function in the human liver and whole-body

International audienceOrganic Anion-Transporting Polypeptides (OATPs) are known to control the liver uptake of many drugs. Non-hepatic expression of OATPs has been reported although functional importance for whole-body pharmacokinetics (WBPK) remains unknown. Glyburide is a well described substrate of several hepatic and non-hepatic OATPs. Dynamic whole-body positron emission tomography (DWB-PET) with [11C]glyburide was performed in humans for determination of the importance of OATPs for liver uptake and WBPK. Seven healthy male subjects (24.7 ± 3.2 years) underwent [$^{11}$]glyburide PET scan with concomitant blood sampling. All subjects underwent baseline [$^{11}$]glyburide PET scan. Five subjects underwent a subsequent [11C]glyburide PET scan after infusion of the potent OATP inhibitor rifampicin (9 mg/kg i.v.). The transfer constant ($k_{uptake}$) of [$^{11}$]glyburide from blood to the liver was estimated using the integration plot method. The tissue exposure of [11C]glyburide was described by the area under the time-activity curve (AUC) and corresponding tissue/blood ratio (AUCR). [$^{11}$]glyburide was barely metabolized in both the baseline and rifampicin conditions. Parent (unmetabolized) [$^{11}$]glyburide accounted for > 90 % of the plasma radioactivity. Excellent correlation was found between radioactive counting in arterial blood samples and in the image-derived input function, in both the baseline and rifampicin conditions (R$^2$ = 97.9 %, p < 0.01). [$^{11}$]glyburide predominantly accumulated in the liver. Rifampicin decreased liver $k_{uptake}$ by 77.3 ± 7.3 %, which increased exposure in blood, kidneys, spleen, myocardium and brain (p < 0.05). No significant change in AUCR was observed except in the liver (p < 0.01). [$^{11}$]glyburide benefits from metabolic stability and high sensitivity to OATP inhibition which enables quantitative determination of OATP function. DWB-PET suggests negligible role for non-hepatic OATPs in controlling the tissue distribution of [$^{11}$]glyburide

Mild pituitary phenotype in 3- and 12-month-old Aip-deficient male mice

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Hyperparathyroidism in Patients With X‐Linked Hypophosphatemia

International audienceX-linked hypophosphatemia (XLH) is characterized by increased activity of circulating FGF23 resulting in renal phosphate wasting and abnormal bone mineralization. Hyperparathyroidism may develop in XLH patients; however, its prevalence, pathogenesis, and clinical presentation are not documented. This observational study (CNIL 171036 v 0) recruited XLH adult patients in a single tertiary referral center. Each patient was explored in standardized conditions and compared with two healthy volunteers, matched for sex, age, and 25-OH vitamin D concentrations. The primary endpoint was the proportion of patients with hyperparathyroidism. The secondary endpoints were the factors influencing serum parathyroid hormone (PTH) concentrations and the prevalence of hypercalcemic hyperparathyroidism. Sixty-eight patients (51 women, 17 men) were enrolled and matched with 136 healthy volunteers. Patients had higher PTH concentrations compared with healthy controls (53.5 ng/L, interquartile range [IQR] 36.7-72.7 versus 36.0 ng/L, IQR 27.7-44.0, p < .0001). Hyperparathyroidism was observed in 17 patients of 68 (25%). In patients, a positive relationship between PTH and calcium concentrations and a negative relationship between PTH and phosphate concentrations were observed. Seven (10%) patients (3 premenopausal women, 1 postmenopausal woman, and 3 men) were diagnosed with hypercalcemic hyperparathyroidism. All underwent parathyroid surgery, with consecutive normalization of calcium and PTH concentrations. Hyperparathyroidism is a frequent complication in XLH adult patients. Disruption of the physiological regulation of PTH secretion contributes to parathyroid disease. Early-onset hypercalcemic hyperparathyroidism can be effectively and safely cured by surgical resection. © 2020 American Society for Bone and Mineral Research

Epicardial and Pericardial Adiposity Without Myocardial Steatosis in Cushing Syndrome

International audienceAbstract Context Cardiovascular disease is the leading cause of death in patients with Cushing syndrome. Cortisol excess and adverse metabolic profile could increase cardiac fat, which can subsequently impair cardiac structure and function. Objective We aimed to evaluate cardiac fat mass and distribution in patients with Cushing syndrome. Methods In this prospective, cross-sectional study, 23 patients with Cushing syndrome and 27 control individuals of comparable age, sex, and body mass index were investigated by cardiac magnetic resonance imaging and proton spectroscopy. Patients were explored before and after biochemical disease remission. Myocardial fat measured by the Dixon method was the main outcome measure. The intramyocardial triglyceride/water ratio measured by spectroscopy and epicardial and pericardial fat volumes were secondary outcome measures. Results No difference was found between patients and controls in intramyocardial lipid content. Epicardial fat mass was increased in patients compared to controls (30.8 g/m2 [20.4-34.8] vs 17.2 g/m2 [13.1-23.5], P &lt; .001). Similarly, pericardial fat mass was increased in patients compared to controls (28.3 g/m2 [17.9-38.0] vs 11.4 g/m2 [7.5-19.4], P = .003). Sex, glycated hemoglobin A1c, and the presence of hypercortisolism were independent determinants of epicardial fat. Pericardial fat was associated with sex, impaired glucose homeostasis and left ventricular wall thickness. Disease remission decreased epicardial fat mass without affecting pericardial fat. Conclusion Intramyocardial fat stores are not increased in patients with Cushing syndrome, despite highly prevalent metabolic syndrome, suggesting increased cortisol-mediated lipid consumption. Cushing syndrome is associated with marked accumulation of epicardial and pericardial fat. Epicardial adiposity may exert paracrine proinflammatory effects promoting cardiomyopathy

Post-acute COVID-19 syndrome

International audienceInfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) pandemic that has resulted in millions of deaths and a major strain on health systems worldwide. Medical treatments for COVID-19 (anticoagulants, corticosteroids, anti-inflammatory drugs, oxygenation therapy and ventilation) and vaccination have improved patient outcomes. The majority of patients will recover spontaneously or after acute-phase management, but clinicians are now faced with long-term complications of COVID-19 including a large variety of symptoms, defined as “post-acute COVID-19 syndrome”. Most studies have focused on patients hospitalised for severe COVID-19, but acute COVID-19 syndrome is not restricted to these patients and exists in outpatients. Given the diversity of symptoms and the high prevalence of persistent symptoms, the management of these patients requires a multidisciplinary team approach, which will result in the consumption of large amounts of health resources in the coming months. In this review, we discuss the presentation, prevalence, pathophysiology and evolution of respiratory complications and other organ-related injuries associated with post-acute COVID-19 syndrome

Syndrome post-COVID-19

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