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Introduction The low prevalence of pituitary diseases makes patient autonomy crucial, and self-management programs should be more common. Objectives To assess the efficacy of an education program for patients with pituitary diseases in terms of patients’ quality of life, satisfaction and goal attainment. Design and methods Adult patients with pituitary disorders were recruited in a tertiary referral center and chose at least three of eight possible sessions on various topics, from disease management to psychosocial issues. Patients were included if they attended at least three sessions between 2012 and 2016 and completed the initial, final, and follow-up questionnaires. Data on quality of life (SF36), satisfaction and goal attainment were analyzed. Results Fifty-three patients were included (33 women; mean age, 53.5 years). There were a significant quality of life improvements in terms of physical and psychic limitation scores at the final assessment that persisted at follow-up evaluation. Most patients reached their objectives, especially those on sharing experiences and improving autonomy and self-confidence. More than half set new objectives at the end of the program, the most popular one being to reinforce their knowledge of their pituitary disease, its evolution and treatment (17.1% of patients). The mean overall satisfaction score was 3.75/4. At follow-up evaluation, patients reported improved self-management of pituitary disease (3.6/5) and improved self-efficacy (3.8/5). Conclusion Individualizing the educational objectives of patients with pituitary disease improves the way they live with their disease. If confirmed in other cohorts, this approach could become the gold standard for education programs in rare endocrine diseases.

Purpose: Combining surgery and medical treatments allows the control of growth hormone hypersecretion in 80% of cases. Our objective was to determine the rate of acromegaly comorbidities once hypersecretion of growth hormone is controlled. Methods: Our retrospective monocentric study was based on 130 patients followed on a regular basis, with acromegaly controlled by medical treatments or cured by surgery or radiation technique. Our main outcome measures were the prevalence of major metabolic complications of acromegaly (diabetes, hypertension, low-density lipoprotein cholesterol, triglycerides) at diagnosis and last follow-up in comparison with French epidemiological data. Results: As expected, controlling hypersecretion significantly improved the metabolic complications of acromegaly. However, the proportion of patients having at least one metabolic complication of acromegaly at last follow-up (mean, 72 months after remission) was 27% for altered glucose tolerance or diabetes, 39% for hypertension, 34.3% for hypercholesterolemia, and 13.3% for hypertriglyceridemia. Interestingly, our data showed that diabetes was the only comorbidity different with a higher prevalence in patients in remission versus a general population of a similar median age (21.6% vs 6.9%, respectively). Conclusions: The follow-up of glucose disorders needs to be maintained on a long-term basis in patients controlled for acromegaly., Comorbidities of acromegaly can persist for several years despite controlled GH levels. Diabetes should be particularly followed and treated independently of the final GH status.

Resume L’acromegalie et la maladie de Cushing predisposent a des complications variees dont beaucoup sont communes aux deux pathologies. Les therapeutiques actuelles permettent un controle de l’hypersecretion chez la grande majorite des patients avec cependant une regression tres variable de la prevalence des complications. Par exemple, sur le plan metabolique, le controle de l’hypersecretion permet la regression du diabete chez plus d’un tiers des patients acromegales et la moitie des patients Cushing sans que ces prevalences rejoignent celles de la population generale. La tension arterielle diminue egalement significativement dans les deux pathologies et rejoint progressivement les chiffres de la population generale. En revanche, si le profil lipidique des patients acromegales s’ameliore progressivement, l’hypertriglyceridemie perdure chez les patients Cushing. De nombreuses autres atteintes (cardio-vasculaires, osseuses, psychologiques avec retentissement sur la qualite de vie) restent presentes, au moins partiellement, chez les patients en remission d’acromegalie ou de maladie de Cushing. Ces sequelles imposent donc une surveillance reguliere allant au-dela de l’evaluation du risque de recidive. L’objectif de cette revue est de mieux definir ces sequelles et de proposer un mode de surveillance adapte centre sur la prise en charge multidisciplinaire de ces patients porteurs de pathologies chroniques. Les donnees presentees ont ete discutees lors du congres europeen d’endocrinologie, Munich 2016, notamment par J.Romijn et E.Valassi.

International audience; Central nervous system hemangioblastomas (CNS-HBs) occur sporadically or as a component of von Hippel-Lindau-VHL syndrome. CNS-HBs share some molecular similarities with pheochromocytomas/paragangliomas (PPGLs) and renal cell carcinomas (RCCs). Recently, hypoxia-inducible factors, particularly somatic HIF2A mutations, have been found to play an important role in the pathogenesis of PPGLs. Somatic mutations in HIF2A have been reported in PPGLs associated with polycythemia, which have been reported to also be present in patients with RCCs and HBs. However, whether CNS-HBs is associated with the presence of a HIF2A mutation is currently uknown. We analyzed somatic HIF2A and VHL mutations in a series of 28 sporadic CNS-HBs. We also investigated the expression of HIF target proteins and hypoxia-associated factor (HAF). Two sporadic CNS-HBs were found to have somatic HIF2A mutations. One tumor had 2 HIF2A missense mutations, one of which was previously described in a PPGL (c.1121 T\textgreaterA, F374Y). The second patient had coexistence of somatic truncated mutations (c.1669 C\textgreaterT, Q557*) in HIF2A together with a VHL mutation. Neither of the two patients had polycythemia at the time of diagnosis. We demonstrate that the novel truncated mutation in HIF2A (Q557*) affects HIF-2α prolyl hydroxylation with its reduced ubiquitination but intact transcriptional activity, resulting in an activating effect. Both CNS-HB samples showed positive expression of VEGFR2/CA9/Glut1 and HAF. Our data support the unique central role of the VHL/HIF-2α signaling pathway in the molecular pathogenesis of CNS-HBs and show for the first time the presence of HIF2A mutations in sporadic HB.

International audience; Von Hippel-Lindau (VHL) syndrome is a hereditary cancer syndrome characterized by a high risk of developing benign and malignant tumors, including central nervous system hemangioblastomas (CNS HBs). For an early diagnosis of VHL, before the occurrence of cancers (especially renal cell carcinoma), it is of huge importance to initiate VHL genetic testing in at-risk patients. The aim of the study was to assess the psychological impact of VHL genetic testing in patients previously diagnosed with a CNS HB. From 1999 until 2015, 55 patients underwent surgery for CNS HBs. Eleven patients were already screened for VHL mutations and 3 patients deceased before the start of the study. From the remaining 42 patients, 24 were accepted to be enrolled in the study. Assessment of psychological impact of VHL genetic testing was performed by measuring anxiety levels, mood disorders, quality of life, and psychological consequences of genetic screening. Twenty-one of the enrolled 24 patients underwent VHL genetic testing and 12 patients came back for the communication of positive genetic results. The baseline psychological status did not differ between these 2 groups. Patients who attended the visit of communication of genetic results had similar anxiety levels compared to those who had not. Furthermore, they also experienced an improvement in the level of anxiety and two QoL dimension scores compared to their baseline status. In summary, there is no evidence of a negative psychosocial impact of VHL genetic testing in patients with a previous history of CNS HB. We, therefore, recommend the recall of patients who have not been previously screened.

Over the last two decades, the understanding of the mechanisms involved in pituitary ontogenesis has largely increased. Since the first description of POU1F1 human mutations responsible for a well-defined phenotype without extra-pituitary malformation, several other genetic defects of transcription factors have been reported with variable degrees of phenotype-genotype correlations. However, to date, despite the identification of an increased number of genetic causes of isolated or multiple pituitary deficiencies, the etiology of most (80-90 %) congenital cases of hypopituitarism remains unsolved. Identifying new etiologies is of importance as a post-natal diagnosis to better diagnose and treat the patients (delayed pituitary deficiencies, differential diagnosis of a pituitary mass on MRI, etc.), and as a prenatal diagnosis to decrease the risk of early death (undiagnosed corticotroph deficiency for instance). The aim of this review is to summarize the main etiologies and phenotypes of combined pituitary hormone deficiencies, associated or not with extra-pituitary anomalies, and to suggest how the identification of such etiologies could be improved in the near future.

International audience; LHX4 is a LIM homeodomain transcription factor involved in the early steps of pituitary ontogenesis. To date, 8 heterozygous LHX4 mutations have been reported as responsible of combined pituitary hormone deficiency (CPHD) in Humans. We identified 4 new LHX4 heterozygous allelic variants in patients with congenital hypopituitarism: W204X, delK242, N271S and Q346R. Our objective was to determine the role of LHX4 variants in patients' phenotypes. Heterologous HEK293T cells were transfected with plasmids encoding for wild-type or mutant LHX4. Protein expression was analysed by Western Blot, and DNA binding by electro-mobility shift assay experiments. Target promoters of LHX4 were cotransfected with wild type or mutant LHX4 to test the transactivating abilities of each variant. Our results show that the W204X mutation was associated with early GH and TSH deficiencies and later onset ACTH deficiency. It led to a truncated protein unable to bind to alpha-Gsu promoter binding consensus sequence. W204X was not able to activate target promoters in vitro. Cotransfection experiments did not favour a dominant negative effect. In contrast, all other mutants were able to bind the promoters and led to an activation similar as that observed with wild type LHX4, suggesting that they were likely polymorphisms. To conclude, our study underlines the need for functional in vitro studies to ascertain the role of rare allelic variants of LHX4 in disease phenotypes. It supports the causative role of the W204X mutation in CPHD and adds up childhood onset ACTH deficiency to the clinical spectrum of the various phenotypes related to LHX4 mutations.

Contexte Le programme d’ETP DEFHYEDU, developpe dans le CRMR d’origine hypophysaire DEFHY, a recu l’agrement de l’ARS fin 2012 (140 patients, mai 2013–mai 2016). Lors du diagnostic educatif, le patient se fixe des objectifs et va choisir des ateliers parmi les 8 proposes couvrant les problematiques rencontrees dans les pathologies hypophysaires : connaissance et gestion du traitement, notamment l’hydrocortisone, vecu de la maladie au quotidien, projection dans l’avenir et complications rencontrees, nutrition et troubles de la satiete, sexualite et fertilite… Un entretien final fait le point sur les competences acquises et restant a conforter. Objectif et methode Analyser de facon quantitative et qualitative (questionnaires de satisfaction, SF36 [avant, fin de programme et >3 mois], commentaires libres) l’impact de ce programme sur les 35 premiers patients ayant complete le programme (12H/23F). Resultats Le score de satisfaction est tres haut : 3,74/4 et une large majorite de patients considere avoir atteint ses objectifs. Le pourcentage de patients qui se fixent de nouveaux objectifs etait de 51,4 % ; pour 71 %, il s’agit de l’amelioration de la connaissance de leur maladie, des traitements et de leur evolution. Cela temoigne d’un processus d’evolution et de changement dans leurs priorites. Concernant la QDV, les patients semblent ressentir moins de limitations dues a leur etat physique a 3 mois (p Conclusion Au vu de ces premiers resultats, le programme DEFHYEDU semble satisfaire les patients porteurs de pathologies hypophysaires et ameliorer sur certains points leur qualite de vie.

Introduction La combinaison de la chirurgie et des traitements medicamenteux permet un controle de l’hypersecretion chez plus de 80 % des patients acromegales. Chez ces patients controles, il importe de connaitre le risque de persistance des complications, pour adapter au mieux la surveillance. Notre objectif etait de determiner la reversibilite de ces complications une fois l’IGF-1 normalisee. Methodes Nous avons inclus 130 patients acromegales gueris par la chirurgie ou controles par un traitement medicamenteux, suivis dans le service d’endocrinologie de l’hopital de la Conception, Marseille, France. Les principales complications de l’acromegalie (diabete, HTA, dyslipidemie, nodules thyroidiens, polypes coliques) ainsi que l’existence de cancers, IDM et AVC ont ete notees au diagnostic, lors de la remission, et lors du dernier suivi (moyenne 58 mois apres le diagnostic). Resultats Le controle de l’hypersecretion permet une amelioration statistiquement significative des complications de l’acromegalie. Cependant, 24 % des patients diabetiques au diagnostic, 33 % des patients avec un LDL eleve, 14 % des patients avec hypertriglyceridemie et 35 % des patients hypertendus, n’avaient pas d’amelioration de ces parametres au dernier suivi malgre la remission de l’acromegalie. Malgre ce profil cardiovasculaire, seulement 3 IDM et 5 AVC ont ete notes. Enfin, chez 47 % des patients, on notait une apparition de nouveaux polypes coliques, et chez 37 % une augmentation du nombre de nodules thyroidiens apres la remission. Conclusion Ce travail souligne la persistance voire l’evolutivite des complications de l’acromegalie, malgre la normalisation de l’IGF-1 justifiant un suivi a long terme dont les patients acromegales doivent etre informes et eduques.

Contexte LHX4 est un facteur de transcription a homeodomaine LIM implique dans les etapes precoces de l’ontogenese hypophysaire. A ce jour, seulement 7 mutations de LHX4 ont ete identifiees comme responsables de deficit hypophysaire combine. Sujets et methodes Quatre nouveaux variants alleliques, a l’etat heterozygote, ont ete identifies parmi des patients porteurs de deficits hypophysaires combines multiples du reseau GENHYPOPIT. Trois patients presentaient une post-hypophyse ectopique. Un des patients presentaient un phenotype hypophysaire atypique avec un deficit corticotrope de survenue retardee et d’aggravation progressive. Le but de ce travail etait de determiner si les mutations retrouvees pouvaient etre impliquees dans le phenotype des patients. Resultats Les transfections basees sur l’activation des promoteurs de la TSHbeta et de POU1F1 ont demontre que la mutation W204X, presente chez le patient porteur d’un phenotype atypique, etait probablement implique dans le phenotype via un phenomene d’haplo-insuffisance. Cette mutation entraine une proteine tronquee avec alteration de l’homeodomaine. Les etudes fonctionnelles complementaires (gel retard) confirment le mecanisme. A l’inverse, les etudes fonctionnelles n’ont pas permis de mettre en evidence d’effet deletere des variants delK242, N271S et Q346R malgre le phenotype evocateur de mutations de facteurs de transcription hypophysaire d’expression precoce. Conclusion Le phenotype des patients porteurs de mutations de LHX4 est tres variable. La mutation W204X ajoute une specificite a ces phenotypes avec une possible aggravation progressive d’un deficit hypophysaire. Ce nouveau phenotype implique la necessite d’une surveillance rapprochee des patients porteurs de ce type de mutations.