Publications by authors named "Philippe Touraine"

124 Publications

Congenital adrenal hyperplasia - current insights in pathophysiology, diagnostics and management.

Endocr Rev 2021 May 7. Epub 2021 May 7.

Division of Pediatric Endocrinology, UT Southwestern Medical Center, Dallas TX, USA.

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders affecting cortisol biosynthesis. Reduced activity of an enzyme required for cortisol production leads to chronic overstimulation of the adrenal cortex and accumulation of precursors proximal to the blocked enzymatic step. The most common form of CAH is caused by steroid 21- hydroxylase deficiency due to mutations in CYP21A2. Since the last publication summarizing CAH in Endocrine Reviews in 2000 there have been numerous new developments. These include more detailed understanding of steroidogenic pathways, refinements in neonatal screening, improved diagnostic measurements utilizing chromatography and mass spectrometry coupled with steroid profiling, and improved genotyping methods. Clinical trials of alternative medications and modes of delivery have been recently completed or are under way. Genetic and cell-based treatments are being explored. A large body of data concerning long-term outcomes in patients affected by CAH, including psychosexual well-being, has been enhanced by the establishment of disease registries. This review provides the reader with current insights in congenital adrenal hyperplasia with special attention to these new developments.
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http://dx.doi.org/10.1210/endrev/bnab016DOI Listing
May 2021

Modified-Release Hydrocortisone in Congenital Adrenal Hyperplasia.

J Clin Endocrinol Metab 2021 Apr;106(5):e2063-e2077

University of Sheffield, Sheffield, UK.

Context: Standard glucocorticoid therapy in congenital adrenal hyperplasia (CAH) regularly fails to control androgen excess, causing glucocorticoid overexposure and poor health outcomes.

Objective: We investigated whether modified-release hydrocortisone (MR-HC), which mimics physiologic cortisol secretion, could improve disease control.

Methods: A 6-month, randomized, phase 3 study was conducted of MR-HC vs standard glucocorticoid, followed by a single-arm MR-HC extension study. Primary outcomes were change in 24-hour SD score (SDS) of androgen precursor 17-hydroxyprogesterone (17OHP) for phase 3, and efficacy, safety and tolerability of MR-HC for the extension study.

Results: The phase 3 study recruited 122 adult CAH patients. Although the study failed its primary outcome at 6 months, there was evidence of better biochemical control on MR-HC, with lower 17OHP SDS at 4 (P = .007) and 12 (P = .019) weeks, and between 07:00h to 15:00h (P = .044) at 6 months. The percentage of patients with controlled 09:00h serum 17OHP (< 1200 ng/dL) was 52% at baseline, at 6 months 91% for MR-HC and 71% for standard therapy (P = .002), and 80% for MR-HC at 18 months' extension. The median daily hydrocortisone dose was 25 mg at baseline, at 6 months 31 mg for standard therapy, and 30 mg for MR-HC, and after 18 months 20 mg MR-HC. Three adrenal crises occurred in phase 3, none on MR-HC and 4 in the extension study. MR-HC resulted in patient-reported benefit including menses restoration in 8 patients (1 on standard therapy), and 3 patient and 4 partner pregnancies (none on standard therapy).

Conclusion: MR-HC improved biochemical disease control in adults with reduction in steroid dose over time and patient-reported benefit.
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http://dx.doi.org/10.1210/clinem/dgab051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063257PMC
April 2021

Puberty and fertility in classic galactosemia.

Endocr Connect 2021 Feb;10(2):240-247

Center for Rare Gynecological Disorders, Centre des Pathologies Gynécologiques Rares, Paris, France.

Classic galactosemia is a rare inborn error of galactose metabolism with a birth prevalence of about 1/30,000-60,000. Long-term complications occurring despite dietary treatment consist of premature ovarian insufficiency (POI) and neurodevelopmental impairments. We performed with the French Reference Centers for Rare Diseases a multisite collaborative questionnaire survey for classic galactosemic patients. Its primary objective was to assess their puberty, pregnancy, gonadotropic axis, and pelvic morphology by ultrasound. The secondary objective was to determine predictive factors for pregnancy without oocyte donation. Completed questionnaires from 103 patients, 56 females (median age, 19 years (3-52 years)) and 47 males (median age, 19 years (3-45 years)), were analyzed. Among the 43 females older than 13 years old, mean age for breast development first stage was 13.8 years; spontaneous menarche occurred in 21/31 females at a mean age of 14.6 years. In these 21 women, 62% had spaniomenorrhea and 7/17 older than 30 years had amenorrhea. All age-groups confounded, FSH was above reference range for 65.7% of the patients, anti-Müllerian hormone and inhibin B were undetectable, and the ovaries were small with few or no follicles detected. Among the 5 females who sought to conceive, 4 had pregnancies. Among the 47 males, 1 had cryptorchidism, all have normal testicular function and none had a desire to conceive children. Thus, spontaneous puberty and POI are both common in this population. Spontaneous menarche seems to be the best predictive factor for successful spontaneous pregnancy.
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http://dx.doi.org/10.1530/EC-21-0013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983486PMC
February 2021

Effects of mitotane on testicular adrenal rest tumors in congenital adrenal hyperplasia due to 21-hydroxylase deficiency: a retrospective series of five patients.

Eur J Endocrinol 2021 Mar;184(3):365-371

AP-HP, IE3M, Hôpital Pitié-Salpêtrière, Department of Endocrinology and Reproductive Medicine and Centre de Référence des Maladies Endocriniennes Rares de la Croissance et du Développement, Paris, France.

We conducted a retrospective study on the long-term effect of mitotane treatment on testicular adrenal rest tumors (TARTs) in five adult patients with classic 21-hydroxylase deficiency. After 60 months of mitotane treatment, a decrease in adrenal steroids was observed in four patients. Testicular ultrasonography showed complete disappearance of TART in two patients, stabilization in two patients and a halving of TART volume in the remaining patient. Sperm count improved notably in two patients who had normal baseline inhibin B levels and small inclusions, thus enabling cryopreservation of the subjects' semen. Four years of follow-up of these two patients after the withdrawal of mitotane showed no recurrence of TART and persistent normal testicular function. In conclusion, mitotane could be used as a last resort in CAH patients in the cases of azoospermia associated with TARTs but normal inhibin B levels, as it can improve long-term endocrine and exocrine testicular function.
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http://dx.doi.org/10.1530/EJE-20-0787DOI Listing
March 2021

Editorial: Travelling in time and space in the heart of Paris.

Ann Endocrinol (Paris) 2020 Dec 13. Epub 2020 Dec 13.

Service d'endocrinologie et des maladies de la reproduction, hôpital Bicêtre, 78, rue du Général-Leclerc, 94275 Le Kremlin-Bicêtre, France.

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http://dx.doi.org/10.1016/j.ando.2020.12.006DOI Listing
December 2020

Idiopathic central precocious puberty in a Klinefelter patient: highlights on gonadotropin levels and pathophysiology.

Basic Clin Androl 2020 Dec 9;30(1):19. Epub 2020 Dec 9.

CHU Clermont-Ferrand, Service d'endocrinologie, diabétologie et maladies métaboliques, 58, rue Montalembert, F-63003, Clermont-Ferrand, France.

Background: Idiopathic central precocious puberty (ICPP) is supposed to be non-existent in a context of testicular destruction that is typically present in Klinefelter syndrome (KS). Herein, we describe a rare case of ICPP in a Klinefelter patient (47,XXY) with 2 maternal X chromosomes. Moreover, we highlight the differences in gonadotropin levels in comparison to males with ICPP and a normal karyotype.

Case Presentation: An 8 years old boy with a history of cryptorchidism was evaluated for precocious puberty (Tanner staging: P2/G3). Both testes measured 25x35mm. His hormonal profile confirmed a central origin of precocious puberty with high serum testosterone (4.3 ng/ml), luteinizing hormone [LH (3.5 UI/l)] and follicle stimulating hormone [FSH (7.7 UI/l)] levels. Luteinizing hormone-releasing hormone (LHRH) test amplified LH and FSH secretion to 24 and 14 UI/l respectively. Brain magnetic resonance imaging (MRI) was normal. No MKRN3 mutation was detected. He was treated for ICPP for two years. During puberty, he suffered from hypergonadotropic hypogonadism leading to the diagnosis of KS (47,XXY karyotype). Chromosomal analysis by fluorescent multiplex polymerase chain reaction (PCR) using X chromosome microsatellite markers identified 2 maternal X chromosomes. Analysing 8 cases of KS developing ICPP (our reported case and 7 other published cases) revealed that these KS patients with ICPP have higher LH and FSH levels during ICPP episode than in ICPP patients with a normal karyotype (ICPP with KS vs ICPP with a normal karyotype: LH levels 9.4 ± 12 vs 1.1 ± 0.6 UI/l; FSH levels 23.1 ± 38.5 vs 2.7 ± 1.5 UI/l). Furthermore, their response to gonadotropin-releasing hormone (GnRH) stimulation is characterized by excessive LH and FSH secretion (LH levels post-GnRH: 58 ± 48 vs 15.5 ± 0.8 UI/l; FSH levels post-GnRH: 49.1 ± 62.1 vs 5.7 ± 3.9 UI/l).

Conclusions: ICPP in boys is extremely rare. The pathophysiology of ICPP in KS is unknown. However, maternal X supplementary chromosome and early testicular destruction may play a significant role in the initiation of ICPP, in part explaining the relative "overrepresentation of ICPP in KS. Thus, karyotype analysis could be considered for boys suffering from ICPP, especially if testicular size is smaller or gonadotropins are significantly elevated.
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http://dx.doi.org/10.1186/s12610-020-00117-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724694PMC
December 2020

Transition of young adults with endocrine and metabolic diseases: the 'TRANSEND' cohort.

Endocr Connect 2021 Jan;10(1):21-28

AP-HP. Sorbonne Université, Hôpital Universitaire Pitié Salpêtrière-Charles Foix, Service d'Endocrinologie et Médecine de la Reproduction, Centre de Maladies Endocriniennes Rares de la Croissance et du Développement, Centre de Pathologies Gynécologiques Rares, Paris, France.

Objective: The transition from paediatric to adult medicine involves risks of poor patient outcomes and of significant losses of patients to follow up. The research aimed to analyse the implementation in an initial cohort of patients of a new programme of transition to adult care based on a case management approach.

Design: A longitudinal study of the case management approach to transition, initiated in a university hospital in France in September 2016.

Methods: Patients with the endocrine or metabolic disease diagnosed during childhood and transferred to adult care were included. The transition programme includes three steps based on case management: liaising with paediatric services, personalising care pathways, and liaising with structures outside the hospital (general practitioners, agencies in the educational and social sector).

Results: The cohort included 500 patients, with malignant brain tumour (n = 56 (11%)), obesity (n = 55 (11%)), type 1 diabetes (n = 54 (11%)), or other disease (n = 335 (67%)). Their median age at transfer was 19, and the sex ratio was 0.5. At median 21 months of follow-up, 439 (88%) had a regular follow-up in or outside the hospital, 47 (9%) had irregular follow-up (absence at the last appointment or no appointment scheduled within the time recommended), 4 had stopped care on doctor's advice, 4 had died, 3 had moved, and 3 had refused care. The programme involved 9615 case management actions; 7% of patients required more than 50 actions. Patients requiring most support were usually those affected by a rare genetic form of obesity.

Conclusions: Case managers successfully addressed the complex needs of patients. Over time, the cohort will provide unprecedented long-term outcome results for patients with various conditions who experienced this form of transition.
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http://dx.doi.org/10.1530/EC-20-0520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923139PMC
January 2021

Positive association between progestins and the evolution of multiple fibroadenomas in 72 women.

Endocr Connect 2020 Jun;9(6):570-577

Department of Endocrinology and Reproductive Medicine, GH La Pitié-Salpêtrière Charles-Foix, Center for Rare Gynecological Diseases, Paris, France.

Objective: Multiple fibroadenomas (MFA) of the breast is a rare benign disease, thus its natural history is poorly understood. The aim of our study was to describe the radiological evolution of MFA and to evaluate the influence of different factors on this evolution.

Methods: This was a longitudinal cohort study. All patients included had two clinical and radiological assessments (breast ultrasound (US) and/or MRI) at least 5 years apart.

Results: Seventy-two women were followed for 7.6 ± 2.1 years. The radiological evolution showed a decrease or stability in the number of fibroadenomas (FA) in 26/44 cases on the MRI and in 38/64 cases on the US. There was a decrease of size in 35/44 cases on the MRI and in 53/64 cases on the US. An increase in the number of FAs was found in 18/44 cases in the MRI and 26/64 cases in the US with, for the majority, a decrease of size (19/26 by MRI and 16/18 by MRI). Older age at the first FA (P < 0.0001) and at the diagnosis of MFA (P < 0.0001), pregnancy (P = 0.003) and progestin use (P < 0.001), particularly lynestrenol (P < 0.0001), had a beneficial effect on the evolution of MFA.

Conclusion: This is the first longitudinal study describing women with MFA. The radiological evolution of MFA seamed favorable and similar to that expected for a single FA. We identified factors influencing the evolution of the disease, including progestin treatments such as lynestrenol, which could have a beneficial effect. Our cohort should be followed further in order to expand our knowledge of MFA, especially concerning the risk of breast cancer.
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http://dx.doi.org/10.1530/EC-20-0012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354733PMC
June 2020

Effect of congenital adrenal hyperplasia treated by glucocorticoids on plasma metabolome: a machine-learning-based analysis.

Sci Rep 2020 06 1;10(1):8859. Epub 2020 Jun 1.

Department of Endocrinology and Reproductive Medicine, Sorbonne Université, AP-HP, Pitié-Salpêtrière Hospital, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Centre de Référence des Pathologies Gynécologiques Rares, ICAN, Paris, France.

Background: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency leads to impaired cortisol biosynthesis. Treatment includes glucocorticoid supplementation. We studied the specific metabolomics signatures in CAH patients using two different algorithms.

Methods: In a case-control study of CAH patients matched on sex and age with healthy control subjects, two metabolomic analyses were performed: one using MetaboDiff, a validated differential metabolomic analysis tool and the other, using Predomics, a novel machine-learning algorithm.

Results: 168 participants were included (84 CAH patients). There was no correlation between plasma cortisol levels during glucocorticoid supplementation and metabolites in CAH patients. Indoleamine 2,3-dioxygenase enzyme activity was correlated with ACTH (rho coefficient = -0.25, p-value = 0.02), in CAH patients but not in controls subjects. Overall, 33 metabolites were significantly altered in CAH patients. Main changes came from: purine and pyrimidine metabolites, branched aminoacids, tricarboxylic acid cycle metabolites and associated pathways (urea, glucose, pentose phosphates). MetaboDiff identified 2 modules that were significantly different between both groups: aminosugar metabolism and purine metabolism. Predomics found several interpretable models which accurately discriminated the two groups (accuracy of 0.86 and AUROC of 0.9).

Conclusion: CAH patients and healthy control subjects exhibit significant differences in plasma metabolomes, which may be explained by glucocorticoid supplementation.
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http://dx.doi.org/10.1038/s41598-020-65897-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264133PMC
June 2020

GGPS1 Mutations Cause Muscular Dystrophy/Hearing Loss/Ovarian Insufficiency Syndrome.

Ann Neurol 2020 08 18;88(2):332-347. Epub 2020 Jun 18.

Botnar Research Centre, National Institute for Health Research Biomedical Research Centre Oxford, University of Oxford, Oxford, United Kingdom.

Objective: A hitherto undescribed phenotype of early onset muscular dystrophy associated with sensorineural hearing loss and primary ovarian insufficiency was initially identified in 2 siblings and in subsequent patients with a similar constellation of findings. The goal of this study was to understand the genetic and molecular etiology of this condition.

Methods: We applied whole exome sequencing (WES) superimposed on shared haplotype regions to identify the initial biallelic variants in GGPS1 followed by GGPS1 Sanger sequencing or WES in 5 additional families with the same phenotype. Molecular modeling, biochemical analysis, laser membrane injury assay, and the generation of a Y259C knock-in mouse were done.

Results: A total of 11 patients in 6 families carrying 5 different biallelic pathogenic variants in specific domains of GGPS1 were identified. GGPS1 encodes geranylgeranyl diphosphate synthase in the mevalonate/isoprenoid pathway, which catalyzes the synthesis of geranylgeranyl pyrophosphate, the lipid precursor of geranylgeranylated proteins including small guanosine triphosphatases. In addition to proximal weakness, all but one patient presented with congenital sensorineural hearing loss, and all postpubertal females had primary ovarian insufficiency. Muscle histology was dystrophic, with ultrastructural evidence of autophagic material and large mitochondria in the most severe cases. There was delayed membrane healing after laser injury in patient-derived myogenic cells, and a knock-in mouse of one of the mutations (Y259C) resulted in prenatal lethality.

Interpretation: The identification of specific GGPS1 mutations defines the cause of a unique form of muscular dystrophy with hearing loss and ovarian insufficiency and points to a novel pathway for this clinical constellation. ANN NEUROL 2020;88:332-347.
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http://dx.doi.org/10.1002/ana.25772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496979PMC
August 2020

Genomic sequencing highlights the diverse molecular causes of Perrault syndrome: a peroxisomal disorder (PEX6), metabolic disorders (CLPP, GGPS1), and mtDNA maintenance/translation disorders (LARS2, TFAM).

Hum Genet 2020 Oct 12;139(10):1325-1343. Epub 2020 May 12.

Reproductive Development Group, Murdoch Children's Research Institute, Melbourne, Australia.

Perrault syndrome is a rare heterogeneous condition characterised by sensorineural hearing loss and premature ovarian insufficiency. Additional neuromuscular pathology is observed in some patients. There are six genes in which variants are known to cause Perrault syndrome; however, these explain only a minority of cases. We investigated the genetic cause of Perrault syndrome in seven affected individuals from five different families, successfully identifying the cause in four patients. This included previously reported and novel causative variants in known Perrault syndrome genes, CLPP and LARS2, involved in mitochondrial proteolysis and mitochondrial translation, respectively. For the first time, we show that pathogenic variants in PEX6 can present clinically as Perrault syndrome. PEX6 encodes a peroxisomal biogenesis factor, and we demonstrate evidence of peroxisomal dysfunction in patient serum. This study consolidates the clinical overlap between Perrault syndrome and peroxisomal disorders, and highlights the need to consider ovarian function in individuals with atypical/mild peroxisomal disorders. The remaining patients had variants in candidate genes such as TFAM, involved in mtDNA transcription, replication, and packaging, and GGPS1 involved in mevalonate/coenzyme Q biosynthesis and whose enzymatic product is required for mouse folliculogenesis. This genomic study highlights the diverse molecular landscape of this poorly understood syndrome.
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http://dx.doi.org/10.1007/s00439-020-02176-wDOI Listing
October 2020

Premature ovarian insufficiency: step-by-step genetics bring new insights.

Fertil Steril 2020 04 4;113(4):767-768. Epub 2020 Mar 4.

Department of Endocrinology and Reproductive Medicine, Center for Rare Endocrine and Gynecological Disorders, Sorbonne Université, Assistance Publique Hopitaux de Paris, Paris, France.

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http://dx.doi.org/10.1016/j.fertnstert.2019.12.032DOI Listing
April 2020

Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia.

Eur J Endocrinol 2019 Nov;181(5):481-488

Department of Pharmacology, Sorbonne Université, INSERM CIC Paris-Est, UNICO AP-HP.6 Cardio-Oncology Program, Pitié-Salpêtrière Hospital, Paris, France.

Background: HLA-G is an immune checkpoint molecule, naturally expressed during pregnancy, playing a critical role in the tolerance of the fetal semi-allograft from the maternal immune system. While HLA-G expression levels are associated with progesterone, the influence of other hormones is still unclear. Congenital adrenal hyperplasia (CAH) represents an adequate model to study the hormonal influence on biomarkers as it leads to impaired cortisol biosynthesis and increased progesterone and androgens production due to 21-hydroxylase enzyme deficiency.

Methods: In a cross-sectional study of CAH patients matched on sex and age with healthy control, the association between circulating levels of soluble HLA-G and hormones was assessed by use of non-parametric analyses tests. Multivariable linear regressions were performed on normalized data.

Results: Overall, 83 CAH patients and 69 healthy controls were included. Among CAH patients, all were under glucocorticoid and 52 (62.6%) were under mineralocorticoid supplementation. Compared to controls, CAH patients had increased HLA-G levels (15 vs 8 ng/mL, P = 0.02). In controls, HLA-G level was independently associated with progesterone and estradiol (β = 0.44 (0.35-1.27) and -0.44 (-0.94, -0.26) respectively, both P values = 0.001). In CAH patients, HLA-G level was independently associated with mineralocorticoid supplementation dosage (β = 0.25 (0.04-0.41), P = 0.001) and estradiol (β = -0.22 (-0.57, -0.02), P < 0.001).

Conclusion: CAH patients had higher HLA-G levels than healthy controls. HLA-G level was positively associated with progesterone and corticosteroid supplementation, and negatively with estradiol. The association between mineralocorticoid, renin and HLA-G levels may suggest a role of the renin-angiotensin system in the expression of soluble HLA-G.
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http://dx.doi.org/10.1530/EJE-19-0379DOI Listing
November 2019

Diabetes Mellitus, Extreme Insulin Resistance, and Hypothalamic-Pituitary Langerhans Cells Histiocytosis.

Case Rep Endocrinol 2019 23;2019:2719364. Epub 2019 Jun 23.

Diabetology-Metabolism Dpt, Sorbonne Université, APHP, Institut Hospitalo-Universitaire de Cardiometabolisme et Nutrition (ICAN), Pitié-Salpêtrière-Charles Foix Hospital, 75013 Paris, France.

Background: Langerhans Cell Histiocytosis (LCH) is a rare inflammatory neoplasm characterized by an infiltration of organs by Langerin + (CD207+) and CD1a+ histiocytes. Diabetes insipidus is a frequent manifestation of the disease, while diabetes mellitus is very rare. We report the first case of a 20-year-old man suffering from hypothalamopituitary histiocytosis and diabetes mellitus with serum anti-insulin receptor antibodies.

Case Presentation: A 20-year-old patient was admitted for the evaluation of growth delay and hyperphagia. HbA1c level and fasting blood glucose were in the normal range. The diagnosis of hypothalamopituitary histiocytosis was based on histological features after biopsy of a large suprachiasmatic lesion identified on magnetic resonance imaging (MRI). Association of vinblastine and purinethol was started followed by a second-line therapy by cladribine. During the follow-up, the patient was admitted for recurrence of hyperglycemic states and extreme insulin resistance. The screening for serum anti-insulin receptor antibodies was positive. Each episode of hyperglycemia appeared to be correlated with tumoral activity and increase in serum anti-insulin receptor antibodies and appeared to be improved when the disease was controlled by chemotherapy.

Conclusion: We report the first description of a hypothalamopituitary histiocytosis associated with serum anti-insulin receptor antibodies, extreme insulin resistance, and diabetes. Parallel evolution of glucose levels and serum anti-insulin receptor antibodies seemed to be the consequence of immune suppressive properties of cladribine.
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http://dx.doi.org/10.1155/2019/2719364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612391PMC
June 2019

Endocrine manifestations in a cohort of 63 adulthood and childhood onset patients with Langerhans cell histiocytosis.

Eur J Endocrinol 2019 Sep;181(3):275-285

Service d'Endocrinologie et Médecine de la Reproduction, Hôpital Universitaire Pitié Salpêtrière - Charles Foix, Sorbonne Université, Faculté de Médecine, Paris, France.

Objective: Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplasm which can infiltrate any organ or tissue. Endocrine involvement has mostly been described in case reports and small retrospective studies. We aimed to describe endocrine manifestations in a large cohort of adulthood onset (AO) and childhood onset (CO) patients with LCH.

Design: Single-center observational study conducted between January 2002 and December 2017 at Pitié-Salpêtrière University Hospital (Paris, France), a tertiary care hospital.

Method: Clinical, biological and morphological evaluations of pituitary, gonadal, adrenal and thyroid function evaluations performed in 63 consecutive patients with LCH (AO patients: 40, CO patients: 23). Fifty-eight patients underwent follow-up assessments.

Results: Complete pituitary evaluation was performed in 38/63 patients (60.3%); at least one anterior pituitary dysfunction (APD) was found in 63.2% of them. In this subgroup of patients, the most prevalent deficiencies were diabetes insipidus (DI) and GHD (55.3% each), followed by gonadotropin deficiency (34.2%) and thyrotropin deficiency (23.7%). In the subgroup of the 25 incompletely evaluated patients, we found DI in 44%, GHD in 50%, gonadotropin deficiency in 30.4% and thyrotropin deficiency in 16%. APD was more common in CO patients (P = 0.003) but was not systematically associated with DI regardless of the age of onset. Endocrine dysfunction was most often permanent; moreover, occurrence of new deficiencies has been described during follow-up.

Conclusion: The spectrum of endocrine disorders appears to be large in LCH (both in AO and CO patients) and should be evaluated carefully at diagnosis and during follow-up. APD was not always associated with DI.
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http://dx.doi.org/10.1530/EJE-19-0177DOI Listing
September 2019

Illicit Upregulation of Serotonin Signaling Pathway in Adrenals of Patients With High Plasma or Intra-Adrenal ACTH Levels.

J Clin Endocrinol Metab 2019 11;104(11):4967-4980

Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Normandie University, UNIROUEN, INSERM, U1239, Rouen, France.

Context: In the human adrenal, serotonin (5-HT), released by mast cells stimulates corticosteroid secretion through activation of type 4 serotonin receptors (5-HT4R). In primary pigmented nodular adrenocortical disease cells, activation of the cAMP/protein kinase A (PKA) pathway by PRKAR1A mutations triggers upregulation of the 5-HT synthesizing enzyme tryptophan hydroxylase (TPH) and the 5-HT4, 5-HT6, and 5-HT7 receptors. Because ACTH stimulates cortisol secretion through activation of PKA, adrenocortical tissues exposed to sustained stimulation by ACTH may harbor increased expression of TPH and 5-HT4/6/7 receptors.

Objective: To investigate the effects of long-term ACTH stimulation on the serotonergic pathway in adrenals of patients with high plasma or intra-adrenal ACTH levels.

Methods: Adrenal tissues were obtained from patients with Cushing disease, ectopic secretion of ACTH [paraneoplastic Cushing syndrome; (paraCS)], 21-hydroxylase deficiency (21-OHD), primary bilateral macronodular adrenal hyperplasia with intra-adrenal ACTH presence, or cortisol-producing adenomas. TPH and 5-HT4/6/7 receptor expression was investigated using RT-PCR and immunochemistry in comparison with normal adrenals. Primary cultured adrenocortical cells originating from a patient with paraCS were incubated with 5-HT and 5-HTR agonists/antagonists.

Results: TPH and/or 5-HT4/6/7 receptors were overexpressed in the different types of tissues. In paraCS cultured cells, the cortisol response to 5-HT was exaggerated compared with normal adrenal cells and the stimulatory action of 5-HT was reduced by 5-HT4R antagonist.

Conclusion: Our results indicate that prolonged activation of the cAMP/PKA pathway by ACTH induces an aberrant serotonergic stimulatory loop in the adrenal cortex that likely participates in the pathogenesis of corticosteroid hypersecretion.
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http://dx.doi.org/10.1210/jc.2019-00425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937520PMC
November 2019

TP63-truncating variants cause isolated premature ovarian insufficiency.

Hum Mutat 2019 07 29;40(7):886-892. Epub 2019 Mar 29.

Reproductive Development, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.

Premature ovarian insufficiency involves amenorrhea and elevated follicle-stimulating hormone before age 40, and its genetic basis is poorly understood. Here, we study 13 premature ovarian insufficiency (POI) patients using whole-exome sequencing. We identify PREPL and TP63 causative variants, and variants in other potentially novel POI genes. PREPL deficiency is a known cause of syndromic POI, matching the patients' phenotype. A role for TP63 in ovarian biology has previously been proposed but variants have been described in multiorgan syndromes, and not isolated POI. One patient with isolated POI harbored a de novo nonsense TP63 variant in the terminal exon and an unrelated patient had a different nonsense variant in the same exon. These variants interfere with the repression domain while leaving the activation domain intact. We expand the phenotypic spectrum of TP63-related disorders, provide a new genotype:phenotype correlation for TP63 and identify a new genetic cause of isolated POI.
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http://dx.doi.org/10.1002/humu.23744DOI Listing
July 2019

Paul Kelly, PhD (1943-2018).

Pituitary 2019 Feb;22(1):1-3

University of Manitoba, Winnipeg, MB, Canada.

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http://dx.doi.org/10.1007/s11102-018-0929-8DOI Listing
February 2019

Gene variants identified by whole-exome sequencing in 33 French women with premature ovarian insufficiency.

J Assist Reprod Genet 2019 Jan 7;36(1):39-45. Epub 2018 Nov 7.

Department of Pathology, University of California, San Francisco, CA, 94143-0794, USA.

Purpose: To investigate the potential genetic etiology of premature ovarian insufficiency (POI).

Methods: Whole-exome sequencing (WES) was done on DNA samples from women diagnosed with POI. Mutations identified were analyzed by in silico tools and were annotated according to the guidelines of the American College of Medical Genetics and Genomics. Plausible variants were confirmed by Sanger sequencing.

Results: Four of the 33 individuals (12%) carried pathogenic or likely pathogenic variants, and 6 individuals carried variants of unknown significance. The genes identified with pathogenic or likely pathogenic variants included PMM2, MCM9, and PSMC3IP.

Conclusions: WES is an efficient tool for identifying gene variants in POI women; however, interpretation of variants is hampered by few exome studies involving ovarian disorders and the need for trio sequencing to determine inheritance and to detect de novo variants.
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http://dx.doi.org/10.1007/s10815-018-1349-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338598PMC
January 2019

Surgery is not superior to dilation for the management of vaginal agenesis in Mayer-Rokitansky-Küster-Hauser syndrome: a multicenter comparative observational study in 131 patients.

Am J Obstet Gynecol 2018 09 21;219(3):281.e1-281.e9. Epub 2018 Jul 21.

Department of Pediatric Endocrinology, Gynecology, and Diabetology, Assistance Publique - Hôpitaux de Paris, Hôpital Necker, Paris, France; Université Paris Descartes, Paris, France.

Background: Vaginal agenesis in Mayer-Rokitansky-Küster-Hauser syndrome can be managed either by various surgeries or dilation. The choice still depends on surgeon's preferences rather than on quality comparative studies and validated protocols.

Objective: We sought to compare dilation and surgical management of vaginal agenesis in Mayer-Rokitansky-Küster-Hauser syndrome, in terms of quality of life, anatomical results, and complications in a large multicenter population.

Study Design: Our multicenter study included 131 patients >18 years, at least 1 year after completing vaginal agenesis management. All had an independent gynecological evaluation including a standardized pelvic exam, and completed the World Health Organization Quality of Life instrument (general quality of life) as well as the Female Sexual Function Index and Female Sexual Distress Scale-Revised (sexual quality of life) scales. Groups were: surgery (N = 84), dilation therapy (N = 26), and intercourse (N = 20). One patient was secondarily excluded because of incomplete surgical data. For statistics, data were compared using analysis of variance, Student, Kruskal-Wallis, Wilcoxon, and Student exact test.

Results: Mean age was 26.5 ± 5.5 years at inclusion. In all groups, World Health Organization Quality of Life scores were not different between patients and the general population except for lower psychosocial health and social relationship scores (which were not different between groups). Global Female Sexual Function Index scores were significantly lower in the surgery and dilation therapy groups (median 26 range [2.8-34.8] and 24.7 [2.6-34.4], respectively) than the intercourse group (30.2 [7.8-34.8], P = .044), which had a higher score only in the satisfaction dimension (P = .004). However, the scores in the other dimensions of Female Sexual Function Index were not different between groups. The Female Sexual Distress Scale-Revised median scores were, respectively, 17 [0-52], 20 [0-47], and 10 [10-40] in the surgery, dilation therapy, and intercourse groups (P = .38), with sexual distress in 71% of patients. Median vaginal depth was shorter in dilatation therapy group (9.6 cm [5.5-12]) compared to surgery group (11 cm [6-15]) and intercourse group (11 cm [6-12.5]) (P = .039), but remained within normal ranges. One bias in the surgery group was the high number of sigmoid vaginoplasties (57/84, 68%), but no differences were observed between surgeries. Only 4 patients achieved vaginas <6.5 cm. Delay between management and first intercourse was 6 months (not significant). Seventy patients (53%) had dyspareunia (not significant), and 17 patients all from the surgery group had an abnormal pelvic exam. In the surgery group, 34 patients (40.5%) had complications, requiring 20 secondary surgeries in 17 patients, and 35 (42%) needed postoperative dilation. In the dilation therapy group, 13 (50%) needed maintenance dilation.

Conclusion: Surgery is not superior to therapeutic or intercourse dilation, bears complications, and should therefore be only a second-line treatment. Psychological counseling is mandatory at diagnosis and during therapeutic management.
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http://dx.doi.org/10.1016/j.ajog.2018.07.015DOI Listing
September 2018

Early central blood pressure elevation in adult patients with 21-hydroxylase deficiency.

J Hypertens 2019 01;37(1):175-181

AP-HP, IE3M, Hôpital Pitié-Salpêtrière, Department of Endocrinology and Reproductive Medicine, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Centre de Référence des Pathologies Gynécologiques Rares, ICAN.

Context: Controversial data exist on cardiovascular damages in patients with congenital adrenal hyperplasia (CAH).

Objective: To assess blood pressure and early cardiovascular damages on a large cohort of adult CAH patients and control individuals.

Design: Case-control study.

Setting: Referral Center for Rare Disease, Pitié Salpêtrière Hospital, Paris, France.

Patients Or Other Participants: Fifty-eight women and 26 men with CAH diagnosed in childhood and 85 controls matched-paired for sex, age and smoking status were prospectively included.

Intervention: Measurement of large arteries and microcirculatory anatomical and functional indices as well as hormonal status and cardiovascular risk factors evaluation.

Main Outcome Measure: The primary objective was to compare carotid intima-media thickness (cIMT) in CAH patients and controls. The secondary objectives were to compare blood pressure (BP), radial augmentation index (rAI), central BP, carotid-femoral pulse wave velocity (PWV), skin microcirculation indices and inflammation parameters in CAH patients and controls.

Results: Although PWV and cIMT were identical in patients and controls, higher rAI (64.6 ± 1.7 vs. 59.9 ± 1.6%, P = 0.02) and higher central SBP (101.8 ± 1.5 vs. 95.1 ± 1.5 mmHg, P < 0.001) were observed in CAH patients. Regarding microcirculatory indices, there was a higher functional resting capacity and a lower anatomical capillary density in CAH patients. In multivariate analysis, we found an independant association between CAH and central SBP elevation.

Conclusion: We found an early rise in central SBP in CAH patients whereas sublinical arterial damages markers were normal. Our study suggest that vascular damages and increased cardiovascular risk could be mainly BP-driven.
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http://dx.doi.org/10.1097/HJH.0000000000001850DOI Listing
January 2019

Challenges of the Transition from Pediatric Care to Care of Adults: "Say Goodbye, Say Hello".

Endocr Dev 2018 8;33:1-9. Epub 2018 Jun 8.

Transition has been defined as "the purposeful, planned movement of adolescents and young adults with chronic physical and medical conditions from child-centered to adult-oriented health care systems." We will here describe the challenges of such a process: challenges coming from the pediatrician, from the adolescent, linked to the disease itself, and those from the parents. We will outline how to overcome those fears and challenges to provide a successful transition process. A key factor to underline that process is that a relationship based on confidence should be established between the pediatrician and the physician for adults, in order for that relationship, based on trust, to be the basis for the transfer of the adolescent from the pediatric system of care to the adult one.
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http://dx.doi.org/10.1159/000487521DOI Listing
July 2018

Increased long QT and torsade de pointes reporting on tamoxifen compared with aromatase inhibitors.

Heart 2018 11 2;104(22):1859-1863. Epub 2018 May 2.

AP-HP, Pitié-Salpêtrière Hospital Department of Pharmacology CIC-1421 Pharmacovigilance Unit INSERM UMR ICAN 1166 Sorbonne Université UPMC, Univ Paris 06, Institute of CArdiometabolism and Nutrition (ICAN), Paris, France.

Objective: A prolonged QTc (LQT) is a surrogate for the risk of torsade de pointes (TdP). QTc interval duration is influenced by sex hormones: oestradiol prolongs and testosterone shortens QTc. Drugs used in the treatment of breast cancer have divergent effects on hormonal status.

Methods: We performed a disproportionality analysis using the European database of suspected adverse drug reaction (ADR) reports to evaluate the reporting OR (ROR χ) of LQT, TdP and ventricular arrhythmias associated with selective oestrogen receptor modulators (SERMs: tamoxifen and toremifene) as opposed to aromatase inhibitors (AIs: anastrozole, exemestane and letrozole). When the proportion of an ADR is greater in patients exposed to a drug (SERMs) compared with patients exposed to control drug (AIs), this suggests an association between the specific drug and the reaction and is a potential signal for safety. Clinical and demographic characterisation of patients with SERMs-induced LQT and ventricular arrhythmias was performed.

Results: SERMs were associated with higher proportion of LQT reports versus AIs (26/8318 vs 11/14851, ROR: 4.2 (2.11-8.55), p<0.001). SERMs were also associated with higher proportion of TdP and ventricular arrhythmia reports versus AIs (6/8318 vs 2/14851, ROR: 5.4 (1.29-26.15), p:0.02; 16/8318 vs 12/14851, ROR: 2.38 (1.15-4.94), p:0.02, respectively). Mortality was 38% in patients presenting ventricular arrhythmias associated with SERMs.

Conclusions: SERMs are associated with more reports of drug-induced LQT, TdP and ventricular arrhythmias compared with AIs. This finding is consistent with oestradiol-like properties of SERMs on the heart as opposed to effects of oestrogen deprivation and testosterone increase induced by AIs.

Trial Registration Number: NCT03259711.
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http://dx.doi.org/10.1136/heartjnl-2017-312934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022857PMC
November 2018

Managing Transition in Patients Treated with Growth Hormone.

Front Endocrinol (Lausanne) 2017 11;8:346. Epub 2017 Dec 11.

Global Medical Affairs, Merck KGaA, Darmstadt, Germany.

Growth hormone (GH) promotes growth in children, but is also essential for bone strength, body composition, metabolic factors, such as lipid profile, and maintenance of quality of life. The Merck KGaA (Germany) funded "360° GH in Europe" meeting, held in Lisbon, Portugal, in June 2016, comprised three sessions entitled "," "," and "." The scientific program covered all stages of pediatric GH treatment, and reported here are the outcomes of the third session of the meeting, which considered transition from pediatric GH treatment to teenage and young adult GH therapy. A large number of patients with chronic diseases, including GH deficiency, drop out of therapy during the transition period. Multiple factors are associated with this, such as lack of understanding of the disease process, insufficient knowledge of treatment options, the patient becoming more independent, and requirement for interaction with a new set of health-care workers. Education regarding disease management and treatment options should be provided from an early age and right through the transition period. However, endocrine specialists will view the transition period differently, depending on whether they are pediatric endocrinologists who mainly deal with congenital diseases, in which auxology is important, or adult endocrinologists who are more concerned with body composition and metabolic factors. View points of both a pediatric and an adult endocrine specialist are presented, together with a case study outlining practical aspects of transition. It was noted in the meeting discussion that having one person to guide a patient through transition from an early age is important, but may be constrained by various factors such as finances, and options will differ by country.
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http://dx.doi.org/10.3389/fendo.2017.00346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732460PMC
December 2017

Complex Association of Sex Hormones on Left Ventricular Systolic Function: Insight into Sexual Dimorphism.

J Am Soc Echocardiogr 2018 02 13;31(2):231-240.e1. Epub 2017 Dec 13.

Sorbonne Universités, UPMC Univ Paris 06, AP-HP, Pitié-Salpêtrière Hospital, Department of Cardiology, Echocardiography Unit, Paris, France; UMR ICAN 1166, Paris, France.

Background: Normal values of left ventricular ejection fraction (LVEF) and absolute values of global longitudinal strain (GLS) are lower in men than in women. Data concerning the association of sex hormone levels on these left ventricular systolic function surrogates are scarce. The aim of this study was to determine the association of sex hormones with systolic left ventricular function in healthy subjects and patients with congenital adrenal hyperplasia (CAH) as a model of testosterone dysregulation.

Methods: Eighty-four adult patients with CAH (58 women; median age, 27 years; interquartile range, 23-36 years) and 84 healthy subjects matched for sex and age were prospectively included. Circulating concentrations of sex hormones were measured within 48 hours of echocardiography with assessment of LVEF and left ventricular longitudinal, radial, and circumferential strain.

Results: LVEF and GLS were higher in healthy women than in healthy men (63.9 ± 4.2% vs 60.9 ± 5.1% [P < .05] and 20.0 ± 1.9% vs 17.9 ± 2.4% [P < .001], respectively), while there was no difference in LVEF or GLS between women and men with CAH (63.9 ± 4.5% vs 63.0 ± 4.6% [P = NS] and 19.4 ± 2.2% vs 18.3 ± 1.8% [P = NS], respectively). Bioavailable testosterone levels were higher in women with CAH than in female control subjects (0.08 ng/mL [interquartile range, 0.04-0.14 ng/mL] vs 0.16 ng/mL [interquartile range, 0.04-0.3 ng/mL], P < .001) and lower in men with CAH than in male control subjects (2.3 ng/mL [interquartile range, 1.3-3 ng/mL] vs 2.9 ng/mL [interquartile range, 2.5-3.4 ng/mL], P < .05). In men, LVEF and GLS were negatively correlated with bioavailable testosterone levels (r = -0.3, P ≤ .05, and r = -0.45, P < .01, respectively), while midventricular radial strain was positively correlated with bioavailable testosterone level (r = 0.38, P < .05). The absolute value of circumferential strain was positively correlated with follicle-stimulating hormone (r = 0.65, P < .0001).

Conclusions: These data support that the existence of sex dimorphism concerning left ventricular systolic cardiac function is significantly associated with testosterone levels.
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http://dx.doi.org/10.1016/j.echo.2017.10.017DOI Listing
February 2018

A common African variant of human connexin 37 is associated with Caucasian primary ovarian insufficiency and has a deleterious effect in vitro.

Int J Mol Med 2018 Feb 16;41(2):640-648. Epub 2017 Nov 16.

University Paris-Sud, University Paris Saclay, Medical Faculty Paris-Sud, Bicêtre Hospital, F-94275 Le Kremlin Bicêtre, France.

Folliculogenesis requires communication between granulosa cells and oocytes, mediated by connexin-based gap junctions. Connexin 37 (Cx37)-deficient female mice are infertile. The present study assessed Cx37 deficiency in patients with primary ovarian insufficiency (POI). A candidate gene study was performed in patients and controls from the National Genotyping Center (Evry, France) including 58 Caucasian patients with idiopathic isolated POI and 142 Caucasian controls. Direct genomic sequencing of the coding regions of the GJA4 gene (encoding Cx37) was performed with the aim to identify a deleterious variant associated with POI and absent in ethnically matched controls. A single Cx37 variant absent in the control population was identified, namely a c.946G>A heterozygous substitution leading to a p.Gly316Ser variant that was present in two POI patients. This variant was absent in all Caucasian controls from various databases, and has been observed exclusively in African populations. This variant was identified to have a dominant negative effect in HeLa cells in vitro to alter connexon function (by 67.2±7.17%), as determined by Gap-fluorescence recovery after photobleaching. The alteration principally resulted from a decrease of cell surface connexons due to altered trafficking (by 47.73±8.59%). In marked contrast to this observation, a p.Pro258Ser variant frequent in all ethnic populations in databases had no functional effect in vitro. In conclusion, the present study reported on a Cx37 variant in two Caucasian POI patients, which was absent in control Caucasian populations, and which had a deleterious effect in vitro. It is therefore suggested that in the genetic context of the Caucasian population, this variant may contribute to POI.
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http://dx.doi.org/10.3892/ijmm.2017.3257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5752242PMC
February 2018

Impact of transition on quality of life in patients with congenital adrenal hyperplasia diagnosed during childhood.

Endocr Connect 2017 10 9;6(7):422-429. Epub 2017 Aug 9.

P Touraine, Endocrinology and reproductive medicine, Hopitaux Universitaires Pitie Salpetriere-Charles Foix, Paris, France.

Background: Health-related quality of life (QoL) in adult patients with congenital adrenal hyperplasia (CAH) has been variously reported. However, there is no study evaluating the impact of transition on quality of life.

Methods: Adult patients with classic or non-classic CAH diagnosed during childhood CAH, born between 1970 and 1990, were recruited from the registers of Pediatric departments belonging to the French reference center for endocrine rare disease. Primary end point was the quality of life (WHOQoL -BREF).

Results: Seventy three patients were included in the study, among them 59/73 (81%) were transferred to adult endocrinologist by their pediatricians for transition. WHOQoL -BREF scores were similar between patients with or without transition to specialist adult services, except for environment dimension score, which was slightly higher in CAH patients without transition. However, CAH patients with a regular follow-up had a better physical health, psychological health and environment score and item global quality of life than the group without regular follow-up after transition.

Conclusion: Regular medical follow-up in adulthood is associated with the transition between pediatric and adult care and with better QoL in adults with CAH.
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http://dx.doi.org/10.1530/EC-17-0094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551429PMC
October 2017

Endocrine perturbations in POEMS syndrome: Misunderstood features of a rare paraneoplastic syndrome.

Ann Endocrinol (Paris) 2017 Jul 8;78(3):190-194. Epub 2017 May 8.

IE3M, endocrinologie et médecine de la reproduction, centre de référence des maladies endocriniennes rares de la croissance, hôpitaux universitaires La Pitié-Salpêtrière-Charles-Foix, AP-HP, 75013 Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.ando.2017.01.004DOI Listing
July 2017