Publications by authors named "Brigitte Delemer"

89 Publications

A novel familial PHP1B variant with incomplete loss-of-methylation at GNAS-A/B and enhanced methylation at GNAS-AS2.

J Clin Endocrinol Metab 2021 Mar 2. Epub 2021 Mar 2.

Université Paris-Saclay, Inserm, Physiologie et physiopathologie endocrinienne, Le Kremlin-Bicêtre, France.

Context: Pseudohypoparathyroidism type 1B (PHP1B), also referred to as inactivating PTH/PTHrP Signaling Disorder (iPPSD), is characterized by proximal renal tubular resistance to parathyroid hormone (PTH) leading to hypocalcemia, hyperphosphatemia and elevated PTH values. Autosomal dominant PHP1B (AD-PHP1B) with loss-of-methylation at the maternal GNAS A/B:TSS-DMR (transcription start site-differentially methylated region) alone can be caused by maternal deletions involving STX16.

Objectives: Characterize a previously not reported AD-PHP1B family with loss-of-methylation at GNAS A/B:TSS-DMR, but without evidence for a STX16 deletion on the maternal allele and assess GNAS-AS2:TSS-DMR methylation.

Patients And Methods: DNAs from 24 patients and 10 controls were investigated. AD-PHP1B patients without STX16 deletion from a single family (n=3), AD-PHP1B patients with STX16 deletion (n=9), sporPHP1B (n=10), unaffected controls (n=10), patUPD20 (n=1), and matUPD20 (n=1). Methylation and copy number analyses were performed by pyrosequencing, MS-MPLA, and MLPA, respectively.

Results: Molecular cloning of PCR-amplified, bisulfite-treated genomic DNA from healthy controls revealed evidence for two distinct GNAS-AS2:TSS-DMR subdomains, named AS2-1 and AS2-2, which showed 16.0±2.3% and 31.0±2.2% methylation, respectively. DNA from affected members of a previously not reported AD-PHP1B family without the known genetic defects revealed incomplete LOM (loss-of-methylation) at GNAS A/B:TSS-DMR, normal methylation at the three well-established maternal and paternal DMRs, and, surprisingly, increased methylation at AS2-1 (32.9±3.5%), but not at AS2-2 (30.5±2.9%).

Conclusion: The distinct methylation changes at the novel GNAS-AS2:TSS-DMR will help characterize further different PHP1B/iPPSD3 variants and will guide the search for underlying genetic defects, which may provide novel insights into the mechanisms underlying GNAS methylation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgab136DOI Listing
March 2021

Total gastrectomy for severe proton pump inhibitor-induced hypomagnesemia in a MEN1/Zollinger Ellison syndrome patient.

Pancreatology 2021 Jan 7;21(1):236-239. Epub 2020 Dec 7.

Department of Gastroenterology and Digestive Oncology, Reims University Hospital, Reims, France.

We report here the first case of life-threatening hypomagnesemia in a Zollinger-Ellison syndrome patient with multiple endocrine neoplasia type 1 (MEN1) syndrome. The severe symptomatic hypomagnesemia proved to be due to proton pump inhibitors (PPIs), but withdrawal of PPIs led to early severe peptic complications despite a substitution by histamine H2-receptor antagonist therapy. Simultaneous management of life-threatening hypomagnesemia, severe gastric acid hypersecretion and MEN1-associated gastrinomas was complex. A total gastrectomy was performed in order to definitely preclude the use of PPIs in this frail patient who was not eligible for curative pancreatoduodenal resection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pan.2020.12.002DOI Listing
January 2021

An inaugural diabetic ketoacidosis with acute pancreatitis during COVID-19.

Acta Diabetol 2021 03 13;58(3):389-391. Epub 2020 Nov 13.

Centre Hospitalier Universitaire de Reims, Service d'Endocrinologie - Diabète - Nutrition, Avenue du Général Koenig, 51092, Reims Cedex, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00592-020-01624-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661328PMC
March 2021

Pegvisomant in combination or pegvisomant alone after failure of somatostatin analogs in acromegaly patients: an observational French ACROSTUDY cohort study.

Endocrine 2021 Jan 28;71(1):158-167. Epub 2020 Sep 28.

Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Centre de Référence des Maladies Rares de l'Hypophyse HYPO, 94275, Le Kremlin-Bicêtre, France.

Objective: After surgery, when somatostatin analogs (SAs) do not normalise IGF-I, pegvisomant (PEG) is indicated. Our aim was to define the medical reasons for the treatment of patients with PEG as monotherapy (M) or combined with SA, either as primary bitherapy, PB (PEG is secondarily introduced after SA) or as secondary bitherapy, SB (SAs secondarily introduced after PEG).

Methods: We retrospectively analysed French data from ACROSTUDY.

Results: 167, 88 and 57 patients were treated with M, PB or SB, respectively, during a median time of 80, 42 and 70 months. The median PEG dose was respectively 15, 10 and 20 mg. Before PEG, the mean IGF-I level did not differ between M and PB but the proportion of patients with suprasellar tumour extension was higher in PB group (67.5% vs. 44.4%, P = 0.022). SB regimen was used preferentially in patients with tumour increase and IGF-I level difficult to normalise under PEG. In both secondary regimens, the decrease of the frequency of PEG's injections, compared to monotherapy was confirmed. However, the mean weekly dose of PEG between M and PB remained the same.

Conclusions: The medical rationale for continuing SAs rather than switching to PEG alone in patients who do not normalise IGF-I under SAs was a tumour concern with suprasellar extension and tumour shrinkage under SA. A potential explanation for introducing SA in association with PEG appears to be a tumour enlargement and difficulties to normalise IGF-I levels under PEG given alone. In both regimens, the prospect of lowering PEG injection frequency favoured the choice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12020-020-02501-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835180PMC
January 2021

Evaluation of Nurses' and Patients' Overall Satisfaction with New and Previous Formulations of Octreotide Long-acting Release (Sandostatin LAR): A French Observational Study.

Adv Ther 2020 09 18;37(9):3901-3915. Epub 2020 Jul 18.

Hepatogastroenterology and Digestive Oncology Unit, University Hospital of Reims, Reims, France.

Introduction: The first long-acting release (LAR) formulation of octreotide was marketed in France in the late 1990s. An injectable formulation of Sandostatin LAR (Novartis SAS) with a new diluent has been developed to facilitate its preparation and administration and to improve its use in practice.

Methods: We conducted an observational, cross-sectional and multicenter study in France whose main outcome was to compare nurses' satisfaction with the preparation and administration of both previous and new formulations of octreotide LAR. Secondary outcomes included assessment of patient satisfaction (quality of life and pain felt during the injection) and product tolerance. Data were collected at two time points (one for the first formulation group and one for the second formulation group) through paper questionnaires administered to physicians, patients and nurses including a visual analog scale (VAS) from 0 (unsatisfied) to 10 (very satisfied).

Results: Results showed that overall nurse satisfaction improved from 5.3 (95% CI 4.9-5.8) with the previous formulation to 7.5 (95% CI 7-7.9) with the new formulation (p < 0.0001). Regarding secondary outcomes, the simplicity of the injection increased (84% for the previous formulation and 94% for the new formulation) and the purge problem disappeared (36% for the previous formulation and 4% for the new formulation).

Conclusion: The improvement due to the new formulation of Sandostatin LAR was reported in terms of handling, ease of use and overall nurse satisfaction. The new formulation greatly reduced treatment administration problems associated with the previous formulation, while maintaining low injection site pain and an equivalent safety profile in both indications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12325-020-01429-4DOI Listing
September 2020

Multivariable Prediction Model for Biochemical Response to First-Generation Somatostatin Receptor Ligands in Acromegaly.

J Clin Endocrinol Metab 2020 09;105(9)

Department of Medicine, Endocrinology section, Pituitary Center Rotterdam, Erasmus University Medical Center, Rotterdam, the Netherlands.

Context: First-generation somatostatin receptor ligands (fg-SRLs) represent the mainstay of medical therapy for acromegaly, but they provide biochemical control of disease in only a subset of patients. Various pretreatment biomarkers might affect biochemical response to fg-SRLs.

Objective: To identify clinical predictors of the biochemical response to fg-SRLs monotherapy defined as biochemical response (insulin-like growth factor (IGF)-1 ≤ 1.3 × ULN (upper limit of normal)), partial response (>20% relative IGF-1 reduction without normalization), and nonresponse (≤20% relative IGF-1 reduction), and IGF-1 reduction.

Design: Retrospective multicenter study.

Setting: Eight participating European centers.

Methods: We performed a meta-analysis of participant data from 2 cohorts (Rotterdam and Liège acromegaly survey, 622 out of 3520 patients). Multivariable regression models were used to identify predictors of biochemical response to fg-SRL monotherapy.

Results: Lower IGF-1 concentration at baseline (odds ratio (OR) = 0.82, 95% confidence interval (CI) 0.72-0.95 IGF-1 ULN, P = .0073) and lower bodyweight (OR = 0.99, 95% CI 0.98-0.99 kg, P = .038) were associated with biochemical response. Higher IGF-1 concentration at baseline (OR = 1.40, (1.19-1.65) IGF-1 ULN, P ≤ .0001), the presence of type 2 diabetes (oral medication OR = 2.48, (1.43-4.29), P = .0013; insulin therapy OR = 2.65, (1.02-6.70), P = .045), and higher bodyweight (OR = 1.02, (1.01-1.04) kg, P = .0023) were associated with achieving partial response. Younger patients at diagnosis are more likely to achieve nonresponse (OR = 0.96, (0.94-0.99) year, P = .0070). Baseline IGF-1 and growth hormone concentration at diagnosis were associated with absolute IGF-1 reduction (β = 0.90, standard error (SE) = 0.02, P ≤ .0001 and β  = 0.002, SE = 0.001, P = .014, respectively).

Conclusion: Baseline IGF-1 concentration was the best predictor of biochemical response to fg-SRL, followed by bodyweight, while younger patients were more likely to achieve nonresponse.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgaa387DOI Listing
September 2020

Efficacy and safety of dopamine agonists in patients treated with antipsychotics and presenting a macroprolactinoma.

Eur J Endocrinol 2020 Aug;183(2):221-231

Assistance Publique Hôpitaux de Paris, Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l'Hypophyse HYPO, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.

Context: In patients treated with antipsychotics, the rare occurrence of a macroprolactinoma represents a therapeutic challenge.

Objective: Our aim was to evaluate the efficacy and psychiatric safety of dopamine agonists (DAs) prescribed for large macroprolactinomas in patients with psychosis treated with antipsychotics.

Design: This was a multicenter (France and Belgium) retrospective study.

Patients: Eighteen patients treated with antipsychotics were included.

Results: Under DA, median PRL levels decreased from 1247 (117-81 132) to 42 (4-573) ng/mL (P = 0.008), from 3850 (449-38 000) to 141 (60-6000) ng/mL (P = 0.037) and from 1664 (94-9400) to 1215 (48-5640) ng/mL (P = 0.56) when given alone (n = 8), before surgery (n = 7), or after surgery (n = 6), respectively. The prolactinoma median largest diameter decreased by 28% (0-57) in patients under DAs alone (P = 0.02) but did not change when given after surgery. Optic chiasm decompression was achieved in 82% of patients. Five patients (28%) were admitted for psychotic relapse while receiving DAs (but three of them had stopped antipsychotic treatment at that time). A more severe underlying psychosis, rather than the DA treatment itself, may explain such psychiatric admissions.

Conclusions: Even if the DA efficacy on PRL levels and tumor volume in patients with macroprolactinoma under antipsychotic drugs is less impressive than that typically observed, it may be considered satisfactory for half of our patients, particularly in cases of optic chiasm compression. Psychotic exacerbation was unusual in these patients, occurring mostly in those with the most severe psychotic forms. DAs may therefore be used as antitumor treatment for macroprolactinoma in patients with visual involvement, severe headaches or invasion into the skull base who receive antipsychotics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EJE-20-0125DOI Listing
August 2020

Congenital Hypogonadotropic Hypogonadism with Anosmia and Gorlin Features Caused by a PTCH1 Mutation Reveals a New Candidate Gene for Kallmann Syndrome.

Neuroendocrinology 2021 20;111(1-2):99-114. Epub 2020 Feb 20.

University Paris-Saclay, Le Kremlin-Bicêtre, France,

Background: Two loci (CHD7 and SOX10) underlying Kallmann syndrome (KS) were discovered through clinical and genetic analysis of CHARGE and Waardenburg syndromes, conditions that include congenital anosmia caused by olfactory bulb (CA/OBs) defects and congenital hypogonadotropic hypogonadism (CHH). We hypothesized that other candidate genes for KS could be discovered by analyzing rare syndromes presenting with these signs. Study Design, Size, Duration: We first investigated a family with Gorlin-Goltz syndrome (GGS) in which affected members exhibited clinical signs suggesting KS. Participants/Materials, Methods: Proband and family members underwent detailed clinical assessment. The proband received detailed neuroendocrine evaluation. Genetic analyses included sequencing the PTCH1 gene at diagnosis, followed by exome analyses of causative or candidate KS/CHH genes, in order to exclude contribution to the phenotypes of additional mutations. Exome analyses in additional 124 patients with KS/CHH probands with no additional GGS signs.

Results: The proband exhibited CA, absent OBs on magnetic resonance imaging, and had CHH with unilateral cryptorchidism, consistent with KS. Pulsatile Gonadotropin-releasing hormone (GnRH) therapy normalized serum gonadotropins and increased testosterone levels, supporting GnRH deficiency. Genetic studies revealed 3 affected family members harbor a novel mutation of PTCH1 (c.838G> T; p.Glu280*). This unreported nonsense deleterious mutation results in either a putative truncated Ptch1 protein or in an absence of translated Ptch1 protein related to nonsense mediated messenger RNA decay. This heterozygous mutation cosegregates in the pedigree with GGS and CA with OBs aplasia/hypoplasia and with CHH in the proband suggesting a genetic linkage and an autosomal dominant mode of inheritance. No pathogenic rare variants in other KS/CHH genes cosegregated with these phenotypes. In additional 124 KS/CHH patients, 3 additional heterozygous, rare missense variants were found and predicted in silico to be damaging: p.Ser1203Arg, p.Arg1192Ser, and p.Ile108Met.

Conclusion: This family suggests that the 2 main signs of KS can be included in GGS associated with PTCH1 mutations. Our data combined with mice models suggest that PTCH1 could be a novel candidate gene for KS/CHH and reinforce the role of the Hedgehog signaling pathway in pathophysiology of KS and GnRH neuron migration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000506640DOI Listing
February 2020

Evolution of macroprolactinomas during pregnancy: A cohort study of 85 pregnancies.

Clin Endocrinol (Oxf) 2020 05 4;92(5):421-427. Epub 2020 Feb 4.

Service d'Endocrinologie - Diabète - Nutrition, Centre Hospitalier Universitaire de Reims, Reims, France.

Objective: Pregnancy in patients with macroprolactinomas has been associated with a higher risk of pituitary tumour growth. However, the incidence and risk factors remain unclear. We aimed to evaluate the evolution of macroprolactinomas during pregnancy and to identify potential risk factors.

Design, Patients And Measurements: This is a two-centre, retrospective, observational study. All patients with macroprolactinomas, treated with a dopamine receptor agonist (DA), and who had at least one pregnancy were included.

Results: There were a total of 85 viable pregnancies in 46 patients with macroprolactinomas. At diagnosis, mean size of pituitary adenomas was 17.9 ± 8.2 mm (10-43 mm) and mean plasma prolactin level was 1012.2 ± 1606.1 µg/L (60-7804 µg/L). Tumour growth-related symptoms were identified 12 times in 9 patients (19.6%) including 3 cases of apoplexy. Restarting, changing and/or increasing DA treatment was effective in 10 cases. Emergency surgery had to be performed twice (due to pituitary apoplexy). Patients with tumour progression tended to present with larger tumours after initial treatment and before pregnancy (9.9 vs 5.9 mm; P = .0504 and 11.5 vs 7.3 mm; P = .0671, respectively), whereas adenoma size at diagnosis did not seem to be a significant factor. The obstetrical outcomes were comparable to the general population.

Conclusions: Symptomatic growth of macroprolactinoma during pregnancy occurred in 19.6% of medically treated patients. This risk seems higher for patients with poor initial tumour response to the DA treatment. Tumour progression is generally well controlled with medical treatment during pregnancy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cen.14162DOI Listing
May 2020

Added value of 18F-fluorocholine positron emission tomography-computed tomography in presurgical localization of hyperfunctioning parathyroid glands after dual tracer subtraction scintigraphy failure: A retrospective study of 47 patients.

Medicine (Baltimore) 2020 Jan;99(2):e18681

Endocrinologie, diabétologie, nutrition, Hôpital Robert Debré, CHU de Reims, Reims, France.

Hyperparathyroidism is a common endocrine disorder. The precise localization of causal parathyroid gland is crucial to guide surgical treatment. Several studies report the added value of 18F-fluorocholine (FCH) positron emission tomography-computed tomography (PET/CT) as second line imaging but rely on suboptimal first-line imaging using 99mTc-sestaMIBI dual phase scintigraphy. The aim of this study is to evaluate the percentage of successful parathyroid localization with FCH PET/CT after failure of a more sensitive first-line detection protocol associating neck ultrasonography and 99mTc-Pertechnetate/99mTc-sestaMIBI dual tracer subtraction scintigraphy.We included retrospectively 47 patients who underwent a FCH PET/CT as second line imaging for biologically proven primary hyperparathyroidism from November 2016 to October 2018 in Godinot Institute (Reims, France). 99mTc-Pertechnetate/99mTc-sestaMIBI dual tracer subtraction scintigraphy and neck ultrasonography were used as first-line imaging and failed to localize the causal parathyroid lesion in all cases.FCH PET/CT demonstrated at least 1 parathyroid target lesion in 29 patients (62%). 21/29 patients underwent surgery. Target lesions corresponded histologically to hyperfunctioning parathyroid glands for all 21 patients and surgery was followed by hyperparathyroidism biological resolution. Calcium serum levels were associated to FCH PET/CT positivity (P = .002) and a trend toward significance was seen for Parathyroid hormone (PTH) levels (P = .09).FCH PET/CT is a promising tool in second-line parathyroid imaging. Large prospective studies and cost-effectiveness analyses are needed to precise its role.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MD.0000000000018681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959899PMC
January 2020

BMPR1A and BMPR1B Missense Mutations Cause Primary Ovarian Insufficiency.

J Clin Endocrinol Metab 2020 04;105(4)

Inserm U1185, Faculté de Médecine Paris Sud, France.

Context: Primary ovarian insufficiency (POI) is a frequently occurring disorder affecting approximately 1% of women under 40 years of age. POI, which is characterized by the premature depletion of ovarian follicles and elevated plasma levels of follicle-stimulating hormone, leads to infertility. Although various etiological factors have been described, including chromosomal abnormalities and gene mutations, most cases remain idiopathic.

Objective: To identify and to functionally validate new sequence variants in 2 genes that play a key role in mammalian ovarian function, BMPR1A and BMPR1B (encoding for bone morphogenic protein receptor), leading to POI.

Methods: The impact on bone morphogenic protein (BMP) signaling of BMPR1A and BMPR1B variants, previously identified by whole-exome sequencing on 69 women affected by isolated POI, was established by different in vitro functional experiments.

Results: We demonstrate that the BMPR1A-p.Arg442His and BMPR1B-p.Phe272Leu variants are correctly expressed and located but lead to an impairment of downstream BMP signaling.

Conclusion: In accordance with infertility observed in mice lacking Bmpr1a in the ovaries and in Bmpr1b-/- mice, our results unveil, for the first time, a link between BMPR1A and BMPR1B variants and the origin of POI. We show that BMP signaling impairment through specific BMPR1A and BMPR1B variants is a novel pathophysiological mechanism involved in human POI. We consider that BMPR1A and BMPR1B variants constitute genetic biomarkers of the origin of POI and have clinical utility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgz226DOI Listing
April 2020

Impaired 11β-Hydroxysteroid Dehydrogenase Type 2 in Glucocorticoid-Resistant Patients.

J Clin Endocrinol Metab 2019 11;104(11):5205-5216

Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche_S U1185, Faculty of Medicine at Université Paris-Sud, University Paris-Sud, Université Paris-Saclay, Le Kremlin Bicêtre, France.

Context: Six patients carrying heterozygous loss-of-function mutations of glucocorticoid (GC) receptor (GR) presented with hypercortisolism, associated with low kalemia, low plasma renin, and aldosterone levels, with or without hypertension, suggesting a pseudohypermineralocorticism whose mechanisms remain unclear. We hypothesize that an impaired activity of the 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2; encoded by the HSD11B2 gene), catalyzing cortisol (F) inactivation, may account for an inappropriate activation of a renal mineralocorticoid signaling pathway in these GC-resistant patients.

Objective: We aim at studying the GR-mediated regulation of HSD11B2.

Design: The HSD11B2 promoter was subcloned and luciferase reporter assays evaluated GR-dependent HSD11B2 regulation, and 11β-HSD2 expression/activity was studied in human breast cancer MCF7 cells, endogenously expressing this enzyme.

Results: Transfection assays revealed that GR transactivated the long (2.1-kbp) HSD11B2 promoter construct, whereas a defective 501H GR mutant was unable to stimulate luciferase activity. GR-mediated transactivation of the HSD11B2 gene was inhibited by the GR antagonist RU486. A threefold increase in HSD11B2 mRNA levels was observed after dexamethasone (DXM) treatment of MCF7 cells, inhibited by RU486 or by actinomycin, supporting a GR-dependent transcription. Chromatin immunoprecipitation further demonstrated a DXM-dependent GR recruitment onto the HSD11B2 promoter. 11β-HSD2 activity, evaluated by the cortisone/F ratio, quantified by liquid chromatography/tandem mass spectrometry, was 10-fold higher in the supernatant of DXM-treated cells than controls, consistent with a GR-dependent stimulation of 11β-HSD2 catalytic activity.

Conclusion: Collectively, we demonstrate that 11β-HSD2 expression and activity are transcriptionally regulated by GR. In the context of GR haploinsufficiency, these findings provide evidence that defective GR signaling may account for apparent mineralocorticoid excess in GC-resistant patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2019-00800DOI Listing
November 2019

Closed-loop insulin delivery in adults with type 1 diabetes in real-life conditions: a 12-week multicentre, open-label randomised controlled crossover trial.

Lancet Digit Health 2019 05 2;1(1):e17-e25. Epub 2019 May 2.

Center for Study and Research for Improvement of the Treatment of Diabetes, Bioparc-Genopole Evry-Corbeil, Evry, France.

Background: Closed-loop insulin delivery systems are expected to become a standard treatment for patients with type 1 diabetes. We aimed to assess whether the Diabeloop Generation 1 (DBLG1) hybrid closed-loop artificial pancreas system improved glucose control compared with sensor-assisted pump therapy.

Methods: In this multicentre, open-label, randomised, crossover trial, we recruited adults (aged ≥18 years) with at least a 2 year history of type 1 diabetes, who had been treated with external insulin pump therapy for at least 6 months, had glycated haemoglobin (HbA) of 10% or less (86 mmol/mol), and preserved hypoglycaemia awareness. After a 2-week run-in period, patients were randomly assigned (1:1) with a web-based system in randomly permuted blocks of two, to receive insulin via the hybrid closed-loop system (DBLG1; using a machine-learning-based algorithm) or sensor-assisted pump therapy over 12 weeks of free living, followed by an 8-week washout period and then the other intervention for 12 weeks. The primary outcome was the proportion of time that the sensor glucose concentration was within the target range (3·9-10·0 mmol/L) during the 12 week study period. Efficacy analyses were done in the modified intention-to-treat population, which included all randomly assigned patients who completed both 12 week treatment periods. Safety analyses were done in all patients who were exposed to either of the two treatments at least once during the study. This trial is registered with ClinicalTrials.gov, number NCT02987556.

Findings: Between March 3, 2017, and June 19, 2017, 71 patients were screened, and 68 eligible patients were randomly assigned to the DBLG1 group (n=33) or the sensor-assisted pump therapy group (n=35), of whom five dropped out in the washout period (n=1 pregnancy; n=4 withdrew consent). 63 patients completed both 12 week treatment periods and were included in the modified intention-to-treat analysis. The proportion of time that the glucose concentration was within the target range was significantly higher in the DBLG1 group (68·5% [SD 9·4] than the sensor-assisted pump group (59·4% [10·2]; mean difference 9·2% [95% CI 6·4 to 11·9]; p<0·0001). Five severe hypoglycaemic episodes occurred in the DBLG1 group and three episodes occurred in the sensor-assisted pump therapy group, which were associated with hardware malfunctions or human error.

Interpretation: The DBLG1 system improves glucose control compared with sensor-assisted insulin pumps. This finding supports the use of closed-loop technology combined with appropriate health care organisation in adults with type 1 diabetes.

Funding: French Innovation Fund, Diabeloop.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2589-7500(19)30003-2DOI Listing
May 2019

Three Consecutive Pregnancies in a Patient with Chronic Autoimmune Thyroid Disease Associated with Hypothyroidism and Extremely High Levels of Anti-Thyrotropin Receptor Antibodies.

Thyroid 2019 05;29(5):743-747

1 Service d'Endocrinologie - Diabète - Nutrition Reims, Centre Hospitalier Universitaire de Reims, Champagne-Ardenne, France.

Thyroid-stimulating hormone (TSH) receptor (TSHR) antibodies (TRAb) can be present in chronic autoimmune thyroiditis. Transplacental TRAb transfer can lead to fetal thyroid dysfunction and serious complications. We report the case of a woman with autoimmune hypothyroidism and extremely high TRAb levels, with blocking and stimulating activities (biological activities characterized with Chinese hamster ovary cells expressing TSHR). At week 22 of her first pregnancy, sonography detected fetal growth retardation and cardiac abnormalities (extreme tachycardia, right ventricular dilatation, pericardial effusion). The mother's TRAb level, assayed later, was 4030 IU/L ( < 10). Delivered via caesarean section gestational week 30, the newborn girl had several malformations, signs of malnutrition, goiter and hyperthyroidism associated with elevated TRAb (1200 IU/L). The newborn died 26 days after delivery. Faced with persistently high TRAb levels and a desire to become pregnant again, the woman was treated with three consecutive 740-MBq activities of iodine-131, which resulted in a decrease in TRAb to 640 IU/L. The patient had two subsequent pregnancies 16 and 72 months after the radioiodine administration. During the close follow-ups, fetal development was normal, and initial TRAb levels during the two pregnancies were 680 and 260 IU/L, respectively, which initially decreased but then increased in late pregnancy. In both cases, labor was induced at 34 weeks. The newborns, mildly hyperthyroid at birth, required carbimazole treatment at days 5 and 2, respectively. The mild hyperthyroidism despite high TRAb levels was likely due to the concomitant presence of stimulating and blocking TRAb. The two girls, now aged 12 and 8 years, are in good health. The mother has no detectable thyroid gland tissue and is euthyroid on levothyroxine (175 μg/d). Her TRAb level gradually decreased to 136 IU/L. This remarkable case illustrates the severe consequences of untreated fetal hyperthyroidism and the need to assay and follow-up TRAb levels in women of reproductive age with autoimmune thyroiditis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/thy.2018.0098DOI Listing
May 2019

Positive Impact of Genetic Test on the Management and Outcome of Patients With Paraganglioma and/or Pheochromocytoma.

J Clin Endocrinol Metab 2019 04;104(4):1109-1118

Assistance Publique, Hôpitaux de Paris, Hôpital Cochin, Service d'Endocrinologie, Centre de Référence Maladies Rares de la Surrénale, Paris, France.

Context: Pheochromocytomas and paragangliomas (PPGLs) are characterized by a strong genetic component, with up to 40% of patients carrying a germline mutation in a PPGL susceptibility gene. International guidelines recommend that genetic screening be proposed to all patients with PPGL.

Objective: Our objective was to evaluate how a positive genetic test impacts the management and outcome of patients with SDHx or VHL-related PPGL.

Design: We performed a multicentric retrospective study involving 221 propositi carrying an SDHB, SDHD, SDHC, or VHL germline mutation. Patients were divided into two groups: genetic patients, who were informed of their genetic status within the year following the first PPGL diagnosis, and historic patients, who only benefited from the genetic test several years after initial PPGL diagnosis.

Results: Genetic patients had better follow-up than historic patients, with a greater number of examinations and a reduced number of patients lost to follow-up (9.6% vs 72%, respectively). During follow-up, smaller (18.7 vs 27.6 mm; P = 0.0128) new PPGLs and metastases as well as lower metastatic spread were observed in genetic patients. Of note, these differences were reversed in the historic cohort after genetic testing. Genetic patients who developed metachronous metastases had a better 5-year survival rate than historic patients (P = 0.0127).

Conclusion: Altogether, our data suggest that early knowledge of genetic status had a positive impact on the management and clinical outcome of patients with a germline SDHx or VHL mutation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2018-02411DOI Listing
April 2019

Daily life, needs and expectations of patients with acromegaly in France: An on-line survey.

Ann Endocrinol (Paris) 2019 Apr 25;80(2):110-116. Epub 2018 Sep 25.

Service d'endocrinologie, diabète-nutrition, CHU de Reims, 51092 Reims cedex, France.

Acromegaly can impair quality of life, but impact on patients' daily life, needs and expectations have been poorly explored.

Objectives: To better understand the impact of acromegaly on patients' daily life, and evaluate their needs and expectations.

Patients And Methods: An on-line questionnaire survey of acromegaly patient and relative community members was conducted on the Carenity website.

Results: Twenty-five patients and 3 relatives, with a mean age of 48.9 years, responded. Diagnosis of acromegaly was recent (60% within 10 years). Signs at diagnosis were mainly clinical (fatigue, headache) and physical changes (acral enlargement). Reported complications comprised morphological changes (93%), bone and joint symptoms (75%) and metabolic disorders (75%). Pain and fatigue impacted the daily life of 61% and 54% patients, respectively. Acromegaly had strong impact on mood (79%), leisure (75%) and social life (71%). Patients mostly got information from specialized websites (71%), their endocrinologist (61%) and patient associations (54%). The information sought was patient testimony (82%), practical advice (64%), and information on clinical trials (61%) and treatments (50%). Patients wished to have patient-physician discussion groups (25%), and better knowledge of acromegaly on the part of those they were in contact with (25%).

Conclusion: Acromegaly has a major impact on patients' daily life and mood. Patients wished their disease to be better known, and advocated setting up discussion groups. This study should encourage acromegaly education programs to adapt the services and information that are needed by acromegalic patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ando.2018.08.006DOI Listing
April 2019

Similarities and differences in the reproductive phenotypes of women with congenital hypogonadotrophic hypogonadism caused by GNRHR mutations and women with polycystic ovary syndrome.

Hum Reprod 2019 Jan;34(1):137-147

University of Paris-Sud and University Paris-Saclay, Le Kremlin-Bicêtre, France.

Study Question: Does the phenotype of women with normosmic congenital hypogonadotrophic hypogonadism (nCHH) and pituitary resistance to GnRH caused by biallelic mutations in the GnRH receptor (GNRHR) (nCHH/bi-GNRHR) differ from that of women with polycystic ovary syndrome (PCOS)?

Summary Answer: Women with nCHH/bi-GNRHR have variable pubertal development but nearly all have primary amenorrhea and an exaggerated LH response to GnRH stimulation, similar to that seen in women with PCOS.

What Is Known Already: Women with nCHH/bi-GNRHR are very rare and their phenotype at diagnosis is not always adequately documented. The results of gonadotrophin stimulation by acute GnRH challenge test and ovarian features have not been directly compared between these patients and women with PCOS.

Study Design, Size, Duration: We describe the phenotypic spectrum at nCHH/bi-GNRHR diagnosis in a series of 12 women. Their reproductive characteristics and acute responses to GnRH were compared to those of 70 women with PCOS.

Participants/materials, Setting, Methods: Patients and controls (healthy female volunteers aged over 18 years) were enrolled in a single French referral centre. Evaluation included clinical and hormonal studies, pelvic ultrasonography and GnRH challenge test. We also functionally characterized two missense GNRHR mutations found in two new consanguineous families.

Main Results And The Role Of Chance: Breast development was highly variable at nCHH/bi-GNRHR diagnosis, but only one patient had undeveloped breasts. Primary amenorrhea was present in all but two cases. In untreated nCHH/bi-GNRHR patients, uterine height (UH) correlated (P = 0.01) with the circulating estradiol level and was shorter than in 23 nulliparous post-pubertal age-matched controls (P < 0.0001) and than in 15 teenagers with PCOS under 20-years-old (P < 0.0001) in which PCOS was revealed by primary amenorrhea or primary-secondary amenorrhea. Unexpectedly, the stimulated LH peak response in nCHH/bi-GNRHR patients was variable, and often normal or exaggerated. Interestingly, the LH peak response was similar to that seen in the PCOS patients, but the latter women had significantly larger mean ovarian volume (P < 0.001) and uterine length (P < 0.001) and higher mean estradiol (P < 0.001), anti-Müllerian hormone (AMH) (P = 0.02) and inhibin-B (P < 0.001) levels. In the two new consaguineous families, the affected nCHH/bi-GNRHR women carried the T269M or Y290F GNRHR missense mutation in the homozygous state. In vitro analysis of GnRHR showed complete or partial loss-of-function of the T269M and Y290F mutants compared to their wildtype counterpart.

Limitations, Reasons For Caution: The number of nCHH/bi-GNRHR patients reported here is small. As this disorder is very rare, an international study would be necessary to recruit a larger cohort and consolidate the phenotypic spectrum observed here.

Wider Implications Of The Findings: In teenagers and young women with primary amenorrhea, significant breast and uterine development does not rule out CHH caused by biallelic GNRHR mutations. In rare patients with PCOS presenting with primary amenorrhea and a mild phenotype, the similar exaggerated pituitary LH responses to GnRH in PCOS and nCHH/bi-GNRHR patients could lead to diagnostic errors. This challenge test should therefore not be recommended. As indicated by consensus and guidelines, careful analysis of clinical presentation and measurements of testosterone circulating levels remain the basis of PCOS diagnosis. Also, analysis of ovarian volume, UH and of inhibin-B, AMH, estradiol and androgen circulating levels could help to distinguish between mild PCOS and nCHH/bi-GNRHR.

Study Funding/competing Interest(s): This study was supported by the French National Research Agency (ANR) grant ANR-09-GENO-017 KALGENOPATH, France; and by the Italian Ministry of Education, University and Research (MIUR) grant PRIN 2012227FLF_004, Italy. The authors declare no conflict of interest.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/humrep/dey339DOI Listing
January 2019

Correction to: Signs and symptoms of acromegaly at diagnosis: the physician's and the patient's perspectives in the ACRO-POLIS study.

Endocrine 2019 01;63(1):130

Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Centre de Référence des Maladies Rares de l'Hypophyse HYPO, F94275, Le Kremlin-Bicêtre, France.

The original version of this article unfortunately contained a mistake in corresponding author name as Philippe Chanson in the affiliation section.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12020-018-1789-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329722PMC
January 2019

Functional evidence implicating NOTCH2 missense mutations in primary ovarian insufficiency etiology.

Hum Mutat 2019 01 22;40(1):25-30. Epub 2018 Oct 22.

Center For Research in Genetics and Genomics (CIGGUR), GENIUROS Research Group, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia.

Primary ovarian insufficiency (POI) is a frequently occurring disease affecting women under 40 years old. Recently, we have analyzed unrelated POI women via whole exome sequencing (WES) and identified NOTCH2 mutations underlying possible functional effects. The present study involved reanalyzing of WES assays. We used in the KGN granulosa-like cell model, a synthetic gene reporter construct driving luciferase gene expression to assess the functional effects of five NOTCH2 mutations identified in POI patients. We found that NOTCH2-p.Ser1804Leu, p.Ala2316Val, and p.Pro2359Ala mutations had a functional impact on the protein's transcriptional activity. The results have demonstrated for the first time that NOTCH2 mutations contribute to POI etiology. We therefore recommend sequencing NOTCH2's open reading frame in large panels of POI patients to establish an accurate genotype-phenotype correlation. We cannot rule out the fact that patients affected by Alagille syndrome carrying NOTCH2 mutations may suffer ovarian dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.23667DOI Listing
January 2019

Signs and symptoms of acromegaly at diagnosis: the physician's and the patient's perspectives in the ACRO-POLIS study.

Endocrine 2019 01 29;63(1):120-129. Epub 2018 Sep 29.

Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Centre de Référence des Maladies Rares de l'Hypophyse HYPO, F94275, Le Kremlin-Bicêtre, France.

Purpose: Acromegaly is characterized by a broad range of manifestations. Early diagnosis is key to treatment success, but is often delayed as symptomatology overlaps with common disorders. We investigated sign-and-symptom associations, demographics, and clinical characteristics at acromegaly diagnosis.

Methods: Observational, cross-sectional, multicenter non-interventional study conducted at 25 hospital departments in France that treat acromegaly (ClinicalTrials.gov: NCT02012127). Adults diagnosed with acromegaly < 5 years were enrolled. Demographic and clinical data were obtained from medical reports and patient questionnaires. Sign-and-symptom associations were assessed by multiple correspondence analysis (MCA).

Results: Overall, 472 patients were included in the analyses. MCA was unsuccessful in identifying sign-and-symptom associations at diagnosis. Endocrinologists (29.5% patients) and other clinical specialists (37.2% patients) were commonly first to suspect acromegaly. Morphologic manifestations (83.7-87.9% patients), snoring syndrome (81.4% patients), and asthenia (79.2% patients) were frequently present at diagnosis; differences were found between sexes for specific manifestations. Rates of discrepancy between patient- and physician-reported manifestations were highest for functional signs. Earliest manifestations prior to diagnosis, according to how they were detected, were enlarged hands and feet (6.4 ± 6.8 and 6.2 ± 6.9 years, functional signs), hypertension (6.6 ± 7.5 years, complementary examination) and carpal/cubital tunnel syndrome (5.7 ± 6.7 years, functional signs with complementary examination).

Conclusions: Results confirm the broad range of manifestations at diagnosis and delay in recognizing the disease. We identified early manifestations and sex differences that may aid physicians in diagnosing acromegaly. Discrepancy rates suggest physicians should obtain the patient's perspective and seek functional signs during diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12020-018-1764-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329724PMC
January 2019

[LY2963016 insulin glargine: The first biosimilar insulin approved in the European Union].

Presse Med 2018 Oct 25;47(10):854-866. Epub 2018 Sep 25.

Lilly France, 92521 Neuilly-sur-Seine, Paris, France.

Biosimilars are not generics. They are similar, but not exactly identical to the biological reference product. The development plan of a biosimilar should assess the physical, chemical and biological properties (quality), as well as toxicological (safety), pharmacodynamic, pharmacokinetic, and clinical (efficacy and safety) characteristics of the biosimilar developed. The development of generics requires bioequivalence studies in healthy volunteers. Abasaglar, a biosimilar of insulin glargine, is the first insulin biosimilar approved in the European Union. Phase III studies, ELEMENT 1 in patients with type 1 diabetes mellitus and ELEMENT 2 in patients with type 2 diabetes mellitus, showed LY2963016 insulin glargine to have similar efficacy and a comparable safety profile to the insulin glargine Lantus. Policies for interchangeability/substitutability between a biosimilar and the reference product are decided at national level in Europe (LFSP, ANSM).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lpm.2018.06.004DOI Listing
October 2018

ATG7 and ATG9A loss-of-function variants trigger autophagy impairment and ovarian failure.

Genet Med 2019 04 19;21(4):930-938. Epub 2018 Sep 19.

Inserm U1185, Faculté de Médecine Paris Sud, Le Kremlin-Bicêtre, France.

Purpose: Primary ovarian insufficiency (POI) is a frequent disorder that affects ~1% of women under 40 years of age. POI, which is characterized by the premature depletion of ovarian follicles and elevated plasma levels of follicle-stimulating hormone (FSH), leads to infertility. Although various etiological factors have been described, including chromosomal abnormalities and gene variants, most cases remain idiopathic. The aim of the present study was to identify and validate functionally new sequence variants in ATG (autophagy-related genes) leading to POI.

Methods: We have reanalyzed, in silico, the exome sequencing data from a previously reported work performed in 69 unrelated POI women. Functional experiments using a classical hallmark of autophagy, the microtubule-associated protein 1 light chain 3β (LC3), were then used to link these genes to this lysosomal degradation pathway.

Results: We venture a functional link between ATG7 and ATG9A variants and POI. We demonstrated that variant ATG7 and ATG9A led to a decrease in autophagosome biosynthesis and consequently to an impairment of autophagy, a key biological process implicated in the preservation of the primordial follicles forming the ovarian reserve.

Conclusion: Our results unveil that impaired autophagy is a novel pathophysiological mechanism involved in human POI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-018-0287-yDOI Listing
April 2019

MFN2-associated lipomatosis: Clinical spectrum and impact on adipose tissue.

J Clin Lipidol 2018 Nov - Dec;12(6):1420-1435. Epub 2018 Jul 25.

Sorbonne Université, Inserm UMR_S 938, Centre de Recherche Saint-Antoine, Institut Hospitalo-Universitaire de Cardio-métabolisme et Nutrition (ICAN), Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Laboratoire Commun de Biologie et Génétique Moléculaires, Paris, France.

Background: Multiple symmetric lipomatosis (MSL) is characterized by upper-body lipomatous masses frequently associated with metabolic and neurological signs. MFN2 pathogenic variants were recently implicated in a very rare autosomal recessive form of MSL. MFN2 encodes mitofusin-2, a mitochondrial fusion protein previously involved in Charcot-Marie-Tooth neuropathy.

Objective: To investigate the clinical, metabolic, tissular, and molecular characteristics of MFN2-associated MSL.

Methods: We sequenced MFN2 in 66 patients referred for altered fat distribution with one or several lipomas or lipoma-like regions and performed clinical and metabolic investigations in patients with positive genetic testing. Lipomatous tissues were studied in 3 patients.

Results: Six patients from 5 families carried a homozygous p.Arg707Trp pathogenic variant, representing the largest reported series of MFN2-associated MSL. Patients presented both lipomatous masses and a lipodystrophic syndrome (lipoatrophy, low leptinemia and adiponectinemia, hypertriglyceridemia, insulin resistance and/or diabetes). Charcot-Marie-Tooth neuropathy was of highly variable clinical severity. Lipomatous tissue mainly contained hyperplastic unilocular adipocytes, with few multilocular cells. It displayed numerous mitochondrial alterations (increased number and size, structural defects). As compared to control subcutaneous fat, mRNA and protein expression of leptin and adiponectin was strikingly decreased, whereas the CITED1 and fibroblast growth factor 21 (FGF21) thermogenic markers were strongly overexpressed. Consistently, serum FGF21 was markedly increased, and F-FDG-PET-scan revealed increased fat metabolic activity.

Conclusion: MFN2-related MSL is a novel mitochondrial lipodystrophic syndrome involving both lipomatous masses and lipoatrophy. Its complex neurological and metabolic phenotype justifies careful clinical evaluation and multidisciplinary care. Low leptinemia and adiponectinemia, high serum FGF21, and increased F-FDG body fat uptake may be disease markers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacl.2018.07.009DOI Listing
October 2019

Early predictors of diabetic retinopathy in type 1 diabetes: The Retinopathy Champagne Ardenne Diabète (ReCAD) study.

J Diabetes Complications 2018 Aug 19;32(8):753-758. Epub 2018 May 19.

Service d'Endocrinologie, Diabète et Nutrition, CHU de Reims, Avenue du Général Koenig, 51092 Reims, France.

Aims: To determine the relationship between early markers of diabetes control and diabetic retinopathy (DR) in type 1 diabetes.

Methods: A historic cohort study was conducted on 712 patients from the CARéDIAB database. HbA and usual metabolic parameters were measured one year after diagnosis of diabetes. First occurrences of severe hypoglycemia and ketoacidosis during follow-up were selected as time-dependent markers of diabetes control. Data were analyzed in a Cox model using SPSS software to predict DR with significance level at p-value <0.05.

Results: In multivariate regression, any diabetic retinopathy was predicted by HbA (HR = 1.38; CI = 1.25-1.52; p < 0.0001), severe hypoglycemia (HR = 3; CI = 1.99-4.52; p < 0.0001), ketoacidosis (HR = 1.96; CI = 1.17-3.22; p = 0.009), and age at diagnosis (HR = 1.016; CI = 1.002-1.031; p = 0.02). Proliferative DR was predicted by HbA (HR = 1.67; CI = 1.51-1.79; p < 0.0001), severe hypoglycemia (HR = 3.67; CI = 2.74-5.25; p < 0.0001), and ketoacidosis (HR = 2.37; CI = 1.56-3.18; p < 0.0001).

Conclusion: This study shows that the failure to achieve diabetes control after the first year of diagnosis as well as early episodes of acute diabetes complications may contribute to the occurrence of diabetic retinopathy in type 1 diabetes patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jdiacomp.2018.05.011DOI Listing
August 2018

A novel mutation in KHDRBS1 in a patient affected by primary ovarian insufficiency.

Clin Endocrinol (Oxf) 2018 Aug 14;89(2):245-246. Epub 2018 Jun 14.

Center for Research in Genetics and Genomics (CIGGUR), School of Medicine and Health Sciences, GENIUROS Research Group, Universidad del Rosario, Bogotá, Colombia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cen.13749DOI Listing
August 2018

Temporal Uptake Patterns of 18F-Fluorocholine Among Hyperfunctioning Parathyroid Glands.

Clin Nucl Med 2018 Jul;43(7):504-505

Service d'Endocrinologie, Diabétologie et Nutrition, Hôpital Universitaire Robert Debré, Reims, France.

Optimal scan time of F-fluorocholine (FCH) PET/CT for localization of hyperfunctioning parathyroid glands is poorly documented. We report a small series of 9 histologically proven hyperfunctioning parathyroid gland with heterogeneous temporal uptake profile. Thirty-minute dynamic acquisition starting just after F-fluorocholine administration and delayed acquisition were recorded. Three different uptake patterns are seen (early washout, stable uptake, late increase) indicating the importance of an early (5-10 minutes) acquisition. A late acquisition (60 minutes) could be useful when the early acquisition is negative. No correlations were noted between uptake profile and histological or genetic results.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/RLU.0000000000002132DOI Listing
July 2018

Pathophysiology of Glucocorticoid Signaling.

Ann Endocrinol (Paris) 2018 Jun 20;79(3):98-106. Epub 2018 Apr 20.

Inserm Umr_S U1185, faculté de médecine Paris-Sud, université Paris-Sud, université Paris-Saclay, 94276 Le Kremlin-Bicêtre, France; Service d'endocrinologie et des maladies de la reproduction, hôpitaux universitaires Paris-Sud, CHU Bicêtre, AH-HP, 94275 Le Kremlin Bicêtre, France. Electronic address:

Glucocorticoids (GC), such as cortisol or dexamethasone, control various physiological functions, notably those involved in development, metabolism, inflammatory processes and stress, and exert most of their effects upon binding to the glucocorticoid receptor (GR, encoded by NR3C1 gene). GC signaling follows several consecutive steps leading to target gene transactivation, including ligand binding, nuclear translocation of ligand-activated GR complexes, DNA binding, coactivator interaction and recruitment of functional transcriptional machinery. Any step may be impaired and may account for altered GC signaling. Partial or generalized glucocorticoid resistance syndrome may result in a reduced level of functional GR, a decreased hormone affinity and binding, a defect in nuclear GR translocation, a decrease or lack of DNA binding and/or post-transcriptional GR modifications. To date, 26 loss-of-function NR3C1 mutations have been reported in the context of hypertension, hirsutism, adrenal hyperplasia or metabolic disorders. These clinical signs are generally associated with biological features including hypercortisolism without negative regulatory feedback loop on the hypothalamic-pituitary-adrenal axis. Patients had often low plasma aldosterone and renin levels despite hypertension. Only one GR gain-of-function mutation has been described associating Cushing's syndrome phenotype with normal urinary-free cortisol. Some GR polymorphisms (ER22/23EK, GR-9β) have been linked to glucocorticoid resistance and a healthier metabolic profile whereas some others seemed to be associated with GC hypersensitivity (N363S, BclI), increasing cardiovascular risk (diabetes type 2, visceral obesity). This review focuses on the earlier findings on the pathophysiology of GR signaling and presents criteria facilitating identification of novel NR3C1 mutations in selected patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ando.2018.03.001DOI Listing
June 2018

Significant prevalence of mutations in incidentally discovered bilateral adrenal hyperplasia: results of the French MUTA-GR Study.

Eur J Endocrinol 2018 Apr 14;178(4):411-423. Epub 2018 Feb 14.

Service d'Endocrinologie-Diabète-Nutrition, Hôpital Robert Debré, CHU Reims, Reims, France.

Background: Recently discovered mutations of gene, encoding for the GR, in patients with glucocorticoid resistance and bilateral adrenal incidentalomas prompted us to investigate whether GR mutations might be associated with adrenal hyperplasia.

Objective: The multicenter French Clinical Research Program (Muta-GR) was set up to determine the prevalence of GR mutations and polymorphisms in patients harboring bilateral adrenal incidentalomas associated with hypertension and/or biological hypercortisolism without clinical Cushing's signs.

Results: One hundred patients were included in whom sequencing revealed five original heterozygous GR mutations that impaired GR signaling . Mutated patients presented with mild glucocorticoid resistance defined as elevated urinary free cortisol (1.7 ± 0.7 vs 0.9 ± 0.8 upper limit of normal range,  = 0.006), incomplete 1 mg dexamethasone suppression test without suppressed 8-AM adrenocorticotrophin levels (30.9 ± 31.2 vs 16.2 ± 17.5 pg/mL) compared to the non-mutated patients. Potassium and aldosterone levels were lower in mutated patients (3.6 ± 0.2 vs 4.1 ± 0.5 mmol/L,  = 0.01, and 17.3 ± 9.9 vs 98.6 ± 115.4 pg/mL,  = 0.0011, respectively) without elevated renin levels, consistent with pseudohypermineralocorticism. characterization of mutated patients' fibroblasts demonstrated GR haploinsufficiency as revealed by below-normal glucocorticoid induction of gene expression. There was no association between GR polymorphisms and adrenal hyperplasia in this cohort, except an over-representation of polymorphism.

Conclusion: The 5% prevalence of heterozygous mutations discovered in our series is higher than initially thought and encourages GR mutation screening in patients with adrenal incidentalomas to unambiguously differentiate from Cushing's states and to optimize personalized follow-up.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EJE-17-1071DOI Listing
April 2018

SFE/SFEDP adrenal insufficiency French consensus: Introduction and handbook.

Ann Endocrinol (Paris) 2018 Feb 12;79(1):1-22. Epub 2018 Jan 12.

Service d'endocrinologie diabétologie pédiatrique, hôpital Robert-Debré, centre de référence des maladies endocriniennes rares de la croissance et du développement, université Paris Diderot, Assistance publique-Hôpitaux de Paris, 48, boulevard Sérurier, 75019 Paris, France.

The French endocrinology society (SFE) and the French pediatric endocrinology society (DFSDP) have drawn up recommendations for the management of primary and secondary adrenal insufficiency in the adult and child, based on an analysis of the literature by 19 experts in 6 work-groups. A diagnosis of adrenal insufficiency should be suspected in the presence of a number of non-specific symptoms except hyperpigmentation which is observed in primary adrenal insufficiency. Diagnosis rely on plasma cortisol and ACTH measurement at 8am and/or the cortisol increase after synacthen administration. When there is a persistant doubt of secondary adrenal insufficiency, insulin hypoglycemia test should be carried out in adults, adolescents and children older than 2 years. For determining the cause of primary adrenal insufficiency, measurement of anti-21-hydroxylase antibodies is the initial testing. An adrenal CT scan should be performed if auto-antibody tests are negative, then assay for very long chain fatty acids is recommended in young males. In children, a genetic anomaly is generally found, most often congenital adrenal hyperplasia. In the case of isolated corticotropin (ACTH) insufficiency, it is recommended to first eliminate corticosteroid-induced adrenal insufficiency, then perform an hypothalamic-pituitary MRI. Acute adrenal insufficiency is a serious condition, a gastrointestinal infection being the most frequently reported initiating factor. After blood sampling for cortisol and ACTH assay, treatment should be commenced by parenteral hydrocortisone hemisuccinate together with the correction of hypoglycemia and hypovolemia. Prevention of acute adrenal crisis requires an education of the patient and/or parent in the case of pediatric patients and the development of educational programs. Treatment of adrenal insufficiency is based on the use of hydrocortisone given at the lowest possible dose, administered several times per day. Mineralocorticoid replacement is often necessary for primary adrenal insufficiency but not for corticotroph deficiency. Androgen replacement by DHEA may be offered in certain conditions. Monitoring is based on the detection of signs of under- and over-dosage and on the diagnosis of associated auto-immune disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ando.2017.12.001DOI Listing
February 2018