Publications by authors named "Jean-Claude Carel"

135 Publications

Fertility of Women Treated during Childhood with Triptorelin (Depot Formulation) for Central Precocious Puberty: The PREFER Study.

Horm Res Paediatr 2021 Mar 26:1-10. Epub 2021 Mar 26.

Université de Paris, AP-HP. Nord Université de Paris, Hôpital Universitaire Robert-Debré, Service d'Endocrinologie Diabétologie Pédiatrique et Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Paris, France.

Background: Gonadotropin-releasing hormone analogues (GnRHa) administered as depot formulations are the standard of care for children with central precocious puberty (CPP). Puberty resumes after treatment discontinuation, but little is known concerning fertility in women who have been treated with GnRHa for CPP during childhood.

Methods: The PREFER (PREcocious puberty, FERtility) study prospectively analysed fertility, via a series of questionnaires, in women treated during childhood with triptorelin (depot formulation) for CPP. Co-primary endpoints were the proportion of women wanting a pregnancy any time before study inclusion and during the follow-up period but not pregnant 6 and 12 months after stopping contraception and the waiting time to pregnancy (WTP).

Results: A total of 574 women were identified, and 194 women were included in the analysis. Although there were not enough data for primary endpoint assessment, few women (1.7%) reported issues with fertility or were unable to become pregnant despite trying to conceive. Most pregnancies (84.4%, 95% CI [67.2-94.7%]) occurred within 1 year of trying to conceive, in line with the WTP for women without previous CPP.

Conclusion: The results, based on a limited sample of patients, suggest that CPP treated with triptorelin does not negatively impact women's fertility in adulthood. These results need to be consolidated with a subsequent study performed when these women will have reached their mid-thirties.
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http://dx.doi.org/10.1159/000513702DOI Listing
March 2021

Prevalence and course of thyroid dysfunction in neonates at high risk of Graves' disease or with non-autoimmune hyperthyroidism.

Eur J Endocrinol 2021 Mar;184(3):431-440

Assistance Publique-Hôpitaux de Paris, Robert Debré University Hospital, Endocrinology-Diabetology Department, Reference Center for Growth and Development Endocrine Diseases, Paris, France.

Objective: Neonatal hyperthyroidism may be caused by a permanent non-autoimmune genetic disorder or, more frequently, by maternally transmitted high serum TRAb levels. Variable thyroid dysfunction may be observed in this second context. We aimed to evaluate the prevalence of neonatal non-autoimmune hyperthyroidism and of the different types of thyroid function in neonates with a high risk of hyperthyroidism due to maternal Graves' disease (GD).

Design And Methods: This observational cohort study included all neonates identified in the database of a single academic pediatric care center, over a period of 13 years, as having non-autoimmune hyperthyroidism or an autoimmune disorder with high TRAb levels (above 6 IU/L) transmitted by their mothers. Patients were classified as having neonatal hyperthyroidism, hypothyroidism, or euthyroidism with a permanent or transient disorder.

Results: Two of the 34 consecutive neonates selected (6%) had permanent non-autoimmune hyperthyroidism due to germline (n = 1) or somatic (n = 1) mutations of the TSH receptor gene. The patients with high serum TRAb levels at birth had transient hyperthyroidism (n = 23), hypothyroidism (primary n = 2, central n = 3) or persistent euthyroidism (n = 4).

Conclusion: These original findings highlight the need for careful and appropriate monitoring of thyroid function in the long term, not only for the rare patients with non-autoimmune neonatal hyperthyroidism, but also for repeat monitoring during the first month of life in neonates with maternally transmitted high TRAb levels, to ensure the early identification of thyrotoxicosis in more than two thirds of cases and to detect primary or central hypothyroidism, thereby potentially decreasing associated morbidity.
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http://dx.doi.org/10.1530/EJE-20-1320DOI Listing
March 2021

SRY-negative 46,XX testicular/ovotesticular DSD: Long-term outcomes and early blockade of gonadotropic axis.

Clin Endocrinol (Oxf) 2021 Apr 26;94(4):667-676. Epub 2020 Dec 26.

Pediatric Endocrinology Department, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Robert Debré Hospital, Assistance publique-Hôpitaux de Paris, Paris, France.

Objective: SRY-negative 46,XX testicular and ovotesticular disorders/differences of sex development (T/OTDSD) represent a very rare and unique DSD condition where testicular tissue develops in the absence of a Y chromosome. To date, very few studies have described the phenotype, clinical and surgical management and long-term outcomes of these patients. Particularly, early blockade of the gonadotropic axis in patients raised in the female gender to minimize postnatal androgenization has never been reported.

Design: Retrospective description of sixteen 46,XX T/OTDSD patients.

Results: Sixteen 46,XX SRY-negative T/OTDSD were included. Most (12/16) were diagnosed in the neonatal period. Sex of rearing was male for six patients and female for ten, while the clinical presentation varied, with an external masculinization score from 1 to 10. Five patients raised as girl were successfully treated with GnRH analog to avoid virilization during minipuberty. Ovotestes/testes were found bilaterally for 54% of the patients and unilaterally for the others (with a contralateral ovary). Gonadal surgery preserved appropriate tissue in the majority of cases. Spontaneous puberty occurred in two girls and one boy, while two boys required hormonal induction of puberty. One of the girls conceived spontaneously and had an uneventful pregnancy. DNA analyses (SNP-array, next-generation sequencing and whole-exome sequencing) were performed. A heterozygous frameshit mutation in the NR2F2 gene was identified in one patient.

Conclusions: This study presents a population of patients with 46,XX SRY-negative T/OTDSD. Early blockade of gonadotropic axis appears efficient to reduce and avoid further androgenization in patients raised as girls.
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http://dx.doi.org/10.1111/cen.14389DOI Listing
April 2021

Prevalence and clinical characteristics of isolated forms of central precocious puberty: a cohort study at a single academic center.

Eur J Endocrinol 2021 Feb;184(2):243-251

Assistance Publique-Hôpitaux de Paris, Robert Debré University Hospital, Endocrinology-Diabetology Department, Reference Center for Growth and Development Endocrine Diseases, Paris, France.

Objective: Isolated central precocious puberty (CPP) includes sporadic, familial and adoption-related forms, and the characterization of its etiology is challenging. This study investigated the prevalence and clinical characteristics of isolated CPP.

Design And Methods: This observational cohort study included all patients (n = 395) with CPP included in the database of a single academic pediatric care center over a period of 11.5 years.

Results: In total, 332 of the 395 patients (84%) had isolated forms of CPP; the proportion of male patients was lower in this group than for non-isolated CPP (4 vs 33%, P < 0.0001). These patients had sporadic (n = 228, 68.5%), familial (n = 82, 25%) or adoption-related (n = 22, 6.5%) forms. Clinical characteristics at diagnosis were similar between groups, but girls with sporadic CPP were older at referral than those with familial or adoption-related CPP (P < 0.02), and birth weight SDS was lower in adopted patients than in those from the sporadic and familial groups (P < 0.01). In the 72 families containing patients with familial forms, both recessive and dominant transmissions were observed between first-degree relatives. Potential maternal or paternal transmission was identified in two-thirds of the studied families, in similar proportions. An autosomal dominant mode of transmission with low penetrance was suggested by the high proportion of affected parents (33 of the 72 families, 46%). Clinical presentation was similar whatever the mode of inheritance.

Conclusion: These findings highlight the need for careful monitoring of the various forms of CPP. Future studies should explore pathophysiological mechanisms, particularly for familial forms.
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http://dx.doi.org/10.1530/EJE-20-0862DOI Listing
February 2021

Long-term mortality after childhood growth hormone treatment: the SAGhE cohort study.

Lancet Diabetes Endocrinol 2020 08;8(8):683-692

Institute of Cancer Research, London, UK.

Background: Recombinant human growth hormone has been used for more than 30 years and its indications have increased worldwide. There is concern that this treatment might increase mortality, but published data are scarce. We present data from the entire dataset of all eight countries of the Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE) consortium, with the aim of studying long-term overall and cause-specific mortality in young adult patients treated with recombinant human growth hormone during childhood and relating this to the underlying diagnosis.

Methods: This cohort study was done in eight European countries (Belgium, France, Germany, Italy, The Netherlands, Sweden, Switzerland, and the UK). Patients were classified a priori based on pre-treatment perceived mortality risk from their underlying disease and followed up for cause-specific mortality. Person-years at risk of mortality and expected rates from general population data were used to calculate standardised mortality ratios (SMRs).

Findings: The cohort comprised 24 232 patients treated with recombinant human growth hormone during childhood, with more than 400 000 patient-years of follow-up. In low-risk patients with isolated growth hormone deficiency or idiopathic short stature, all-cause mortality was not significantly increased (SMR 1·1, 95% CI 0·9-1·3). In children born small for gestational age, all-cause mortality was significantly increased when analysed for all countries (SMR 1·5, CI 1·1-1·9), but this result was driven by the French subcohort. In patients at moderate or high risk, mortality was increased (SMR 3·8, 3·3-4·4; and 17·1, 15·6-18·7, respectively). Mortality was not associated with mean daily or cumulative doses of recombinant human growth hormone for any of the risk groups. Cause-specific mortality from diseases of the circulatory and haematological systems was increased in all risk groups.

Interpretation: In this cohort, the largest, to our knowledge, with long-term follow-up of patients treated with recombinant human growth hormone during childhood, all-cause mortality was associated with underlying diagnosis. In patients with isolated growth hormone deficiency or idiopathic short stature, recombinant human growth hormone treatment was not associated with increased all-cause mortality. However, mortality from certain causes was increased, emphasising the need for further long-term surveillance.

Funding: European Union.
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http://dx.doi.org/10.1016/S2213-8587(20)30163-7DOI Listing
August 2020

Low-dose IL-2 in children with recently diagnosed type 1 diabetes: a Phase I/II randomised, double-blind, placebo-controlled, dose-finding study.

Diabetologia 2020 09 1;63(9):1808-1821. Epub 2020 Jul 1.

Clinical Investigation Center for Biotherapies and Inflammation-Immunopathology-Biotherapy Department (i2B), AP-HP.Sorbonne Université, Pitié-Salpêtrière Hospital, 83 Bd de l'Hôpital, F-75013, Paris, France.

Aims/hypothesis: Low-dose IL-2 (ld-IL2) selectively activates and expands regulatory T cells (Tregs) and thus has the potential to skew the regulatory/effector T (Treg/Teff) cell balance towards improved regulation. We investigated which low doses of IL-2 would more effectively and safely activate Tregs during a 1 year treatment in children with recently diagnosed type 1 diabetes.

Methods: Dose Finding Study of IL-2 at Ultra-low Dose in Children With Recently Diagnosed Type 1 Diabetes (DF-IL2-Child) was a multicentre, double-blinded, placebo-controlled, dose-finding Phase I/II clinical trial conducted in four centres at university hospitals in France: 24 children (7-14 years old) with type 1 diabetes diagnosed within the previous 3 months were randomly assigned 1:1:1:1 to treatment by a centralised randomisation system, leading to a 7/5/6/6 patient distribution of placebo or IL-2 at doses of 0.125, 0.250 or 0.500 million international units (MIU)/m, given daily for a 5 day course and then fortnightly for 1 year. A study number was attributed to patients by an investigator unaware of the randomisation list and all participants as well as investigators and staff involved in the study conduct and analyses were blinded to treatments. The primary outcome was change in Tregs, expressed as a percentage of CD4 T cells at day 5. It pre-specified that a ≥60% increase in Tregs from baseline would identify Treg high responders.

Results: There were no serious adverse events. Non-serious adverse events (NSAEs) were transient and mild to moderate. In treated patients vs placebo, the commonest NSAE was injection site reaction (37.9% vs 3.4%), whereas other NSAEs were at the same level (23.3% vs 19.2%). ld-IL2 induced a dose-dependent increase in the mean proportion of Tregs, from 23.9% (95% CI -11.8, 59.6) at the lowest to 77.2% (44.7, 109.8) at the highest dose, which was significantly different from placebo for all dose groups. However, the individual Treg responses to IL-2 were variable and fluctuated over time. Seven patients, all among those treated with the 0.250 and 0.500 MIU m day doses, were Treg high responders. At baseline, they had lower Treg proportions in CD4 cells than Treg low responders, and serum soluble IL-2 receptor α (sIL-2RA) and vascular endothelial growth factor receptor 2 (VEGFR2) levels predicted the Treg response after the 5 day course. There was no significant change in glycaemic control in any of the dose groups compared with placebo. However, there was an improved maintenance of induced C-peptide production at 1 year in the seven Treg high responders as compared with low responders.

Conclusions/interpretation: The safety profile at all doses, the dose-dependent effects on Tregs and the observed variability of the Treg response to ld-IL2 in children with newly diagnosed type 1 diabetes call for use of the highest dose in future developments. The better preservation of insulin production in Treg high responders supports the potential of Tregs in regulating autoimmunity in type 1 diabetes, and warrants pursuing the investigation of ld-IL2 for its treatment and prevention.

Trial Registration: ClinicalTrials.gov NCT01862120.

Funding: Assistance Publique-Hôpitaux de Paris, Investissements d'Avenir programme (ANR-11-IDEX-0004-02, LabEx Transimmunom and ANR-16-RHUS-0001, RHU iMAP) and European Research Council Advanced Grant (FP7-IDEAS-ERC-322856, TRiPoD).
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http://dx.doi.org/10.1007/s00125-020-05200-wDOI Listing
September 2020

Socioeconomic Status of Newborns and Hospital Efficiency: Implications for Hospital Payment Methods.

Value Health 2020 03 4;23(3):335-342. Epub 2019 Dec 4.

AP-HP, Hôtel Dieu, URC Eco Ile-de-France, Paris, France; AP-HP, Hôpital Robert Debré, Unité d'Epidémiologie Clinique, Paris, France; Université de Paris, French National Institute of Health and Medical Research, Épidémiologie clinique et évaluation économique applique aux populations vulnérables, Paris, France; French National Institute of Health and Medical Research, Paris, France.

Objectives: Studies have shown a consistent impact of socioeconomic status at birth for both mother and child; however, no study has looked at its impact on hospital efficiency and financial balance at birth, which could be major if newborns from disadvantaged families have an average length of stay (LOS) longer than other newborns. Our objective was therefore to study the association between socioeconomic status and hospital efficiency and financial balance in that population.

Methods: A study was carried out using exhaustive national hospital discharge databases. All live births in a maternity hospital located in mainland France between 2012 and 2014 were included. Socioeconomic status was estimated with an ecological indicator and efficiency by variations in patient LOS compared with different mean national LOS. Financial balance was assessed at the admission level through the ratio of production costs and revenues and at the hospital level by the difference in aggregated revenues and production costs for said hospital. Multivariate regression models studied the association between those indicators and socioeconomic status.

Results: A total of 2 149 454 births were included. LOS was shorter than the national means for less disadvantaged patients and longer for the more disadvantaged patients, which increased when adjusted for gestational age, birth weight, and severity. A 1% increase in disadvantaged patients in a hospital's case mix significantly increased the probability that the hospital would be in deficit by 2.6%.

Conclusions: Reforms should be made to hospital payment methods to take into account patient socioeconomic status so as to improve resource allocation efficiency.
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http://dx.doi.org/10.1016/j.jval.2019.10.008DOI Listing
March 2020

Factors Affecting Loss to Follow-Up in Children and Adolescents with Chronic Endocrine Conditions.

Horm Res Paediatr 2019 5;92(4):254-261. Epub 2020 Feb 5.

Assistance Publique-Hôpitaux de Paris, Robert Debré University Hospital, Department of Pediatric Endocrinology and Diabetology, Reference Center for Growth and Development Endocrine Diseases, Paris, France.

Objective: Most children with endocrine diseases require long-term continuity of care. We investigated the prevalence of loss to follow-up (LTFU) in pediatric patients with chronic endocrine diseases and the risk factors associated with LTFU.

Methods: This observational cohort study included all children with chronic endocrine diseases included in the database of a single academic pediatric care center over a period of 8 years. LTFU was defined as a lack of attendance at clinical visits for over 2 years, for unknown reasons.

Results: LTFU was recorded for 154 of the 1,067 patients included (14%). Median age at diagnosis was 5.8 (0.3-11.8) vs. 1.2 (0.0-6.9) years, and age at last visit was 14.1 (9.7-16.1) vs. 11.7 (6.1-15.8) years, for the LTFU and no-LTFU groups, respectively. In multivariate analysis, the risk of LTFU increased with age at diagnosis (OR 1.18; 95% CI 1.12-1.24) and was higher for patients diagnosed before 2006 (vs. after 2006; OR 4.80; 95% CI 3.00-7.66), with fewer visits in the last 3 years (OR 0.72; 95% CI 0.65-0.80; p < 0.0001) and a lower health insurance classification (OR 1.79; 95% CI 1.10-2.89; p = 0.02). The risk of LTFU was higher for patients with isolated growth hormone deficiency than for those with other endocrine conditions, such as multiple pituitary deficiencies, hypogonadotropic hypogonadism, Turner syndrome, or thyroid, adrenal, or gonadal disorders (OR 5.24; 95% CI 1.13-24.37; p = 0.03).

Conclusion: This study provides the first epidemiological data for LTFU in children and adolescents with chronic endocrine diseases. It should facilitate the targeting of interventions to improve adherence to medical care and healthcare organization during the pediatric period.
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http://dx.doi.org/10.1159/000505517DOI Listing
May 2020

Association of Pediatric Inpatient Socioeconomic Status With Hospital Efficiency and Financial Balance.

JAMA Netw Open 2019 10 2;2(10):e1913656. Epub 2019 Oct 2.

Unité de Recherche Clinique en Économie de la Santé Eco Ile de France, Hôtel Dieu, Assistance Publique-Hôpitaux de Paris, Paris, France.

Importance: In health care systems in which hospital reimbursement is based on a national mean length of stay (LOS), disadvantaged patients with an increased LOS may be a source of inefficiency. This implication has been reported in adult patients, but pediatric data have been scarce.

Objective: To examine the association of patient socioeconomic status with hospital efficiency and financial balance in pediatrics.

Design, Setting, And Participants: This cohort study obtained data from the French national hospital discharge database covering a 3-year period, from January 1, 2012, to December 31, 2014. Statistical analyses were performed between June 2016 and December 2018. All inpatient stays in hospital pediatric wards in mainland France by children older than 28 days or younger than 18 years (n = 4 121 187) were included. Admissions with coding errors or missing values for social disadvantage and/or cost calculations were excluded.

Exposure: Social disadvantage was estimated with an ecological indicator, the FDep, available at the patient's postcode of residence and divided into national quintiles.

Main Outcomes And Measures: Efficiency was assessed through the variations in patient LOS compared with different national mean LOS (for pediatric patients, pediatric patients with a similar condition, and pediatric patients with a similar condition and severity level). Hospital financial balance was assessed at the admission level through the ratio of production costs to revenues and at the hospital level through the difference between aggregated revenues and production costs. Multivariate regression models examined the association between these indicators and socioeconomic status.

Results: A total of 4 121 187 admissions were included (2 336 540 [56.7%] male; mean [SD] age, 7.4 [5.8] years). In all, 1 561 219 patients (37.9%) were in the 2 most disadvantaged quintiles. Patient LOS was shorter than the national mean LOS (mean [SD], 1.73 [4.21] days) for patients in the least disadvantaged quintile and longer for those in the more disadvantaged quintile (mean [SD], 1.67 [4.33] days vs 1.82 [4.14] days). This difference was higher for diagnosis related groups that included both adult and pediatric patients (mean [SD], 1.46 [4.22] days vs 1.61 [4.13] days) compared with those dedicated to pediatric patients (2.22 [4.13] days vs 2.12 [4.53] days). Patients in the most disadvantaged quintile were associated with a 3.2% increase in LOS (odds ratio, 1.0322; 95% CI, 1.0302-1.0341) compared with the national mean LOS. Social disadvantage was also associated with a significant increase in financial deficit for hospitals with 20% to 60% of patients in the 2 most disadvantaged quintiles (estimate: -€146 389; 95% CI, -€279 566 to -€13 213).

Conclusions And Relevance: Patient socioeconomic status appears to be statistically significantly associated with an increase in LOS and cost in French hospitals with pediatric departments. This finding suggests that initiating reform in hospital payment methods may improve resource allocation efficiency and equity in access to pediatric care.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.13656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813670PMC
October 2019

Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome.

Genet Med 2020 01 24;22(1):150-159. Epub 2019 Jul 24.

Human Developmental Genetics Unit, Institut Pasteur, Paris, France.

Purpose: XY individuals with disorders/differences of sex development (DSD) are characterized by reduced androgenization caused, in some children, by gonadal dysgenesis or testis regression during fetal development. The genetic etiology for most patients with 46,XY gonadal dysgenesis and for all patients with testicular regression syndrome (TRS) is unknown.

Methods: We performed exome and/or Sanger sequencing in 145 individuals with 46,XY DSD of unknown etiology including gonadal dysgenesis and TRS.

Results: Thirteen children carried heterozygous missense pathogenic variants involving the RNA helicase DHX37, which is essential for ribosome biogenesis. Enrichment of rare/novel DHX37 missense variants in 46,XY DSD is highly significant compared with controls (P value = 5.8 × 10). Five variants are de novo (P value = 1.5 × 10). Twelve variants are clustered in two highly conserved functional domains and were specifically associated with gonadal dysgenesis and TRS. Consistent with a role in early testis development, DHX37 is expressed specifically in somatic cells of the developing human and mouse testis.

Conclusion: DHX37 pathogenic variants are a new cause of an autosomal dominant form of 46,XY DSD, including gonadal dysgenesis and TRS, showing that these conditions are part of a clinical spectrum. This raises the possibility that some forms of DSD may be a ribosomopathy.
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http://dx.doi.org/10.1038/s41436-019-0606-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944638PMC
January 2020

Hyponatremia in children under 100 days old: incidence and etiologies.

Eur J Pediatr 2019 Sep 13;178(9):1353-1361. Epub 2019 Jul 13.

Assistance Publique-Hôpitaux de Paris (AP-HP), Department of Pediatric Endocrinology and Diabetology, and Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Hôpital Universitaire Robert-Debré, F-75019, Paris, France.

Hyponatremia is one of the most common electrolyte disorders in hospitalized children. The underlying mechanisms are poorly understood and potentially multifactorial, making management difficult, particularly in neonates. This retrospective study aimed to determine the incidence and etiologies of hyponatremia in hospitalized children under the age of 100 days, in our pediatric tertiary care hospital over a 1-year period. The etiology of hyponatremia was determined by reviewing the data noted in each patient's medical reports. Neonatal hyponatremia had a prevalence of 4.3% (86/2012 patients) and was mostly hospital-acquired (74/86 patients). Fifty-nine patients (68.9%) were preterm neonates. The etiology was iatrogenic in 26 cases (30.2%). In other cases, hyponatremia was due to transient (23 patients, 26.7%) or genetic abnormalities of the renal mineralocorticoid pathway (3 patients, 3.4%), SIADH (12 patients, 14%), digestive disease (3 patients, 3.5%), acute renal failure (3 patients, 3.5%), or heart failure (1 patient, 1.2%).Conclusion: Our findings confirm that hyponatremia is a frequent electrolyte disorder in neonates. Various mechanisms underlie this condition, most of which could be prevented by optimized management. The prevalence of genetic hypoaldosteronism and pseudohypoaldosteronism was higher than expected. We provide a simple diagram to help physicians identify the mechanisms underlying neonatal hyponatremia. What is Known: • In neonates, hyponatremia may be multifactorial, making it difficult to treat. • Newborns display partial resistance to aldosterone, and preterms have a defect in aldosterone secretion. What is New: • Four percent of hospitalized neonates had hyponatremia, 86% hospital-acquired. Hyponatremia was due to a transient or constitutional defect of the mineralocorticoid pathway in 26/86 patients (30%) which is higher than expected. • We propose a tree diagram for improving the management of hyponatremia in neonates.
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http://dx.doi.org/10.1007/s00431-019-03406-8DOI Listing
September 2019

Contribution of functionally assessed GHRHR mutations to idiopathic isolated growth hormone deficiency in patients without GH1 mutations.

Hum Mutat 2019 11 6;40(11):2033-2043. Epub 2019 Aug 6.

Genetic Department, INSERM UMR_S933, Hôpital Trousseau, Sorbonne Université, AP-HP, Paris, France.

Isolated growth hormone deficiency (IGHD) is a rare condition mainly caused by mutations in GH1. The aim of this study was to assess the contribution of GHRHR mutations to IGHD in an unusually large group of patients. All GHRHR coding exons and flanking intronic regions were sequenced in 312 unrelated patients with nonsyndromic IGHD. Functional consequences of all newly identified missense variants were assessed in vitro (i.e., study of the expression of recombinant GHRHRs and their ability to activate the cyclic adenosine monophosphate (cAMP) signaling pathway). Genotype-phenotype correlation analyses were performed according to the nature of the identified mutation. We identified 20 different disease-causing GHRHR mutations (truncating and missense loss-of-function mutations), among which 15 are novel, in 24 unrelated patients. Of note, about half (13/24) of those patients represent sporadic cases. The clinical phenotype of patients with at least one missense GHRHR mutation was found to be indistinguishable from that of patients with bi-allelic truncating mutations. This study, which unveils disease-causing GHRHR mutations in 8% (24/312) of IGHD cases, identifies GHRHR as the second IGHD gene most frequently involved after GH1. The finding that 8% of IGHD cases without GH1 mutations are explained by GHRHR molecular defects (including missense mutations), together with the high proportion of sporadic cases among those patients, has important implications for genetic counseling.
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http://dx.doi.org/10.1002/humu.23847DOI Listing
November 2019

Is there an optimal strategy for real-time continuous glucose monitoring in pediatrics? A 12-month French multi-center, prospective, controlled randomized trial (Start-In!).

Pediatr Diabetes 2019 05 6;20(3):304-313. Epub 2019 Feb 6.

Pediatric Endocrinology and Diabetology Department and Centre de Référence des Maladies Endocriniennes Rares de la Croissance, CHU Robert Debré, AP-HP, Paris, France.

Aim: To compare the efficacy of three strategies for real-time continuous glucose monitoring (RT-CGM) over 12 months in children and adolescents with type 1 diabetes.

Methods: A French multicenter trial (NCT00949221) with a randomized, controlled, prospective, open, and parallel-group design was conducted. After 3 months of RT-CGM, patients were allocated to one of three groups: return to self-monitoring of blood glucose, continuous CGM (80% of the time), or discontinuous CGM (40% of the time). The primary outcome was hemoglobin A1c (HbA1c) levels from 3 to 12 months. The secondary outcomes were acute metabolic events, hypoglycemia, satisfaction with CGM and cost.

Results: We included 151 subjects, aged 2 to 17 years, with a mean HbA1c level of 8.5% (SD0.7; 69 mmol/mol). The longitudinal change in HbA1c levels was similar in all three groups, at 3, 6, 9 and 12 months. The medical secondary endpoints did not differ between groups. The rate of severe hypoglycemia was significantly lower than that for the pretreatment year for the entire study population. Subjects reported consistent use and good tolerance of the device, regardless of age or insulin treatment. The use of full-time RT-CGM for 3 months costs the national medical insurance system €2629 per patient.

Conclusion: None of the three long-term RT-CGM strategies evaluated in pediatric type 1 diabetes was superior to the others in terms of HbA1c levels. CGM-use for 3 months decreased rates of severe hypoglycemia. Our results confirm the feasibility of long-term RT-CGM-use and the need to improve educational support for patients and caregivers.
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http://dx.doi.org/10.1111/pedi.12820DOI Listing
May 2019

High prevalence of syndromic disorders in patients with non-isolated central precocious puberty.

Eur J Endocrinol 2018 Dec;179(6):373-380

Assistance Publique-Hôpitaux de Paris, Robert Debré University Hospital, Endocrinology-Diabetology Department, Reference Center for Endocrine Growth and Developmental Diseases, Paris, France.

Objective Non-idiopathic CPP is caused by acquired or congenital hypothalamic lesions visible on MRI or is associated with various complex genetic and/or syndromic disorders. This study investigated the different types and prevalence of non-isolated CPP phenotypes. Design and Methods This observational cohort study included all patients identified as having non-idiopathic CPP in the database of a single academic pediatric care center over a period of 11.5 years. Patients were classified on the basis of MRI findings for the CNS as having either hypothalamic lesions or complex syndromic phenotypes without structural lesions of the hypothalamus. Results In total, 63 consecutive children (42 girls and 21 boys) with non-isolated CPP were identified. Diverse diseases were detected, and the hypothalamic lesions visible on MRI (n = 28, 45% of cases) included hamartomas (n = 17; either isolated or with an associated syndromic phenotype), optic gliomas (n = 8; with or without neurofibromatosis type 1), malformations (n = 3) with interhypothalamic adhesions (n = 2; isolated or associated with syndromic CNS midline abnormalities, such as optic nerve hypoplasia, ectopic posterior pituitary) or arachnoid cysts (n = 1). The patients with non-structural hypothalamic lesions (n = 35, 55% of cases) had narcolepsy (n = 9), RASopathies (n = 4), encephalopathy or autism spectrum disorders with or without chromosomal abnormalities (n = 15) and other complex syndromic disorders (n = 7). Conclusion Our findings suggest that a large proportion (55%) of patients with non-isolated probable non-idiopathic CPP may have complex disorders without structural hypothalamic lesions on MRI. Future studies should explore the pathophysiological relevance of the mechanisms underlying CPP in these disorders.
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http://dx.doi.org/10.1530/EJE-18-0613DOI Listing
December 2018

Monogenic forms of lipodystrophic syndromes: diagnosis, detection, and practical management considerations from clinical cases.

Curr Med Res Opin 2019 03 9;35(3):543-552. Epub 2018 Nov 9.

d Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Robert Debré , Service d'endocrinologie diabétologie pédiatrique, Centre de Compétence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité (PRISIS) , Paris , France.

Background: Lipodystrophic syndromes are rare diseases of genetic or acquired origin characterized by partial or generalized lack of body fat. Early detection and diagnosis are crucial to prevent and manage associated metabolic dysfunctions, i.e. insulin resistance, dyslipidemia, fatty liver, and diabetes, and to provide appropriate genetic counseling. By means of several representative case studies, this article illustrates the diagnostic and management challenges of lipodystrophic syndromes.

Review: Berardinelli-Seip congenital lipodystrophy (BSCL) is typically diagnosed at birth, or soon thereafter, with generalized lipoatrophy and hepatomegaly secondary to hepatic steatosis. Physicians must also consider this diagnosis in adults with atypical non-autoimmune diabetes, hypertriglyceridemia, and a lean and muscular phenotype. The BSCL1 subtype due to mutations in the AGPAT2 gene can have an unusual presentation, especially in neonates and infants. Particular attention should be paid to infants presenting failure to thrive who also have hepatomegaly and metabolic derangements. The BSCL2 sub-type due to mutations in the BSCL gene tends to be more severe than BSCL1, and is characterized by greater fat loss, mild intellectual disability, earlier onset of diabetes, and higher incidence of premature death. Effective management from an earlier age may moderate the natural disease course. Partial lipodystrophies may easily be confused with common central obesity and/or metabolic syndrome. In patients with unexplained pancreatitis and hypertriglyceridemia, lipodystrophies such as familial partial lipodystrophy type 2 (FPLD2; Dunnigan type, due to LMNA mutations) should be considered. Oral combined contraceptives, which can reveal the disease by inducing severe hypertriglyceridemia, are contraindicated. Endogenous estrogens may also lead to "unmasking" of the FPLD2 phenotype, which often appears at puberty, and is more severe in females than males.

Conclusions: Diet and exercise, adapted to age and potential comorbidities, are essential prerequisites for therapeutic management of lipodystrophic syndromes. Metreleptin therapy can be useful to manage lipodystrophy-related metabolic complications.
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http://dx.doi.org/10.1080/03007995.2018.1533459DOI Listing
March 2019

Risk of Meningioma in European Patients Treated With Growth Hormone in Childhood: Results From the SAGhE Cohort.

J Clin Endocrinol Metab 2019 03;104(3):658-664

Dutch Growth Research Foundation, Rotterdam, Netherlands.

Context: There has been concern that GH treatment of children might increase meningioma risk. Results of published studies have been inconsistent and limited.

Objective: To examine meningioma risks in relation to GH treatment.

Design: Cohort study with follow-up via cancer registries and other registers.

Setting: Population-based.

Patients: A cohort of 10,403 patients treated in childhood with recombinant GH in five European countries since this treatment was first used in 1984. Expected rates from national cancer registration statistics.

Main Outcome Measures: Risk of meningioma incidence.

Results: During follow-up, 38 meningiomas occurred. Meningioma risk was greatly raised in the cohort overall [standardized incidence ratio (SIR) = 75.4; 95% CI: 54.9 to 103.6], as a consequence of high risk in subjects who had received radiotherapy for underlying malignancy (SIR = 658.4; 95% CI: 460.4 to 941.7). Risk was not significantly raised in patients who did not receive radiotherapy. Risk in radiotherapy-treated patients was not significantly related to mean daily dose of GH, duration of GH treatment, or cumulative dose of GH.

Conclusions: Our data add to evidence of very high risk of meningioma in patients treated in childhood with GH after cranial radiotherapy, but suggest that GH may not affect radiotherapy-related risk, and that there is no material raised risk of meningioma in GH-treated patients who did not receive radiotherapy.
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http://dx.doi.org/10.1210/jc.2018-01133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334265PMC
March 2019

Diagnosis and management of hyperthyroidism from prenatal life to adolescence.

Best Pract Res Clin Endocrinol Metab 2018 08 5;32(4):373-386. Epub 2018 Apr 5.

Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Robert Debré, Service d'Endocrinologie Diabétologie Pédiatrique, Centre de Référence des Maladies Endocriniennes de la Croissance et du développement, F-75019, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, F-75019, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 1141, DHU PROTECT, F-75019, Paris, France.

Hyperthyroidism in children is a rare heterogeneous syndrome characterized by excessive thyroid hormone production. Its manifestations differ according to disease severity. For all forms of hyperthyroidism, treatment aims to restore a euthyroid state, enabling the child to demonstrate appropriate metabolism, growth, and neurocognitive development. Graves' disease is the most frequent cause of hyperthyroidism in children. Treatment modalities include antithyroid drugs, with the advantage that prolonged treatment for several years can be followed by freedom from medical intervention in about 40-50% of cases. It may also be treated with radioactive iodine or, less frequently, thyroidectomy, these more radical treatments both necessitating subsequent lifelong levothyroxine treatment. Particular care is required in the management of pregnant women with Graves' disease. Fetal and neonatal forms of hyperthyroidism are transient and rare, but nevertheless serious. Here, we provide an overview of the best approach to hyperthyroidism diagnosis and management, from fetal development to adolescence.
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http://dx.doi.org/10.1016/j.beem.2018.03.014DOI Listing
August 2018

Should 45,X/46,XY boys with no or mild anomaly of external genitalia be investigated and followed up?

Eur J Endocrinol 2018 Sep 4;179(3):181-190. Epub 2018 Jul 4.

Pediatric Endocrinology Department, CHU Robert Debré, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Assistance-Publique Hôpitaux de Paris and Université Paris Diderot, Sorbonne Paris Cité, Paris, France.

Objective: Few studies of patients with a 45,X/46,XY mosaicism have considered those with normal male phenotype. The purpose of this study was to evaluate the clinical outcome of 45,X/46,XY boys born with normal or minor abnormalities of external genitalia, notably in terms of growth and pubertal development.

Methods: Retrospective longitudinal study of 40 patients followed between 1982 and 2017 in France.

Results: Twenty patients had a prenatal diagnosis, whereas 20 patients had a postnatal diagnosis, mainly for short stature. Most patients had stunted growth, with abnormal growth spurt during puberty and a mean adult height of 158 ± 7.6 cm, i.e. -2.3 DS with correction for target height. Seventy percent of patients presented Turner-like syndrome features including cardiac (6/23 patients investigated) and renal malformations (3/19 patients investigated). Twenty-two patients had minor abnormalities of external genitalia. One patient developed a testicular embryonic carcinoma, suggesting evidence of partial gonadal dysgenesis. Moreover, puberty occurred spontaneously in 93% of patients but 71% ( = 5) of those evaluated at the end of puberty presented signs of declined Sertoli cell function (low inhibin B levels and increased FSH levels).

Conclusion: This study emphasizes the need to identify and follow-up 45,X/46,XY patients born with normal male phenotype until adulthood, as they present similar prognosis than those born with severe genital anomalies. Currently, most patients are diagnosed in adulthood with azoospermia, consistent with our observations of decreased testicular function at the end of puberty. Early management of these patients may lead to fertility preservation strategies.
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http://dx.doi.org/10.1530/EJE-18-0309DOI Listing
September 2018

Early Determinants of Thyroid Function Outcomes in Children with Congenital Hypothyroidism and a Normally Located Thyroid Gland: A Regional Cohort Study.

Thyroid 2018 08 30;28(8):959-967. Epub 2018 Jul 30.

1 Department of Pediatric Endocrinology Diabetology, Reference Centre for Endocrine Growth and Development Diseases, Assistance Publique-Hôpitaux de Paris, Robert Debré University Hospital , Paris, France .

Background: An increase in the incidence of congenital hypothyroidism (CH) with a normally located gland has been reported worldwide. Affected individuals display transient or permanent CH during follow-up in childhood. This study aimed to determine the prevalence of transient CH and to investigate the possibility of distinguishing between transient and permanent CH in early infancy.

Methods: This observational cohort study included all patients identified by systematic neonatal screening for CH in the northern Parisian region between 2002 and 2012 and treated for CH with a normally sited gland. A standardized data collection form was completed prospectively at diagnosis. Patients were classified during follow-up as having transient or permanent CH.

Results: Of the 92 patients initially treated for CH with a normally located gland during the neonatal period, 49 (54%) had a transient form of CH after the cessation of levothyroxine (LT4) treatment at 1.5 (0.6-3.2) years of age. Multivariate analysis revealed that transient CH was associated with a lower likelihood of having a first-degree family history of CH (p = 0.03) and a lower LT4 dose at six months of age (p = 0.03) than permanent CH. Sex, ethnicity, neonatal problems (e.g., prematurity, being small for gestational age, and/or neonatal distress), iodine status, coexisting malformations, initial CH severity, and thyroid morphology at diagnosis had no effect. Receiver operating characteristics curve analysis showed that a cutoff of 3.2 μg/kg/day for LT4 dose requirement at six months of age had a sensitivity of 71% and a specificity of 79% for predicting transient CH, with values below this threshold considered predictive of transient CH.

Conclusion: In patients with CH and a normally located gland, these findings highlight the need to evaluate LT4 dose requirements early, at six months of age, particularly in patients with no family history of CH, for early identification of the approximately 50% of patients for whom treatment should be stopped.
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http://dx.doi.org/10.1089/thy.2018.0154DOI Listing
August 2018

How Should We Assess Glycemic Variability in Type 1 Diabetes? Contribution of Principal Component Analysis for Interstitial Glucose Indices in 142 Children.

Diabetes Technol Ther 2018 06;20(6):440-447

1 AP-HP, Hôpital Universitaire Robert Debré , Departement of Pediatric Endocrinology and Diabetology and Centre de référence des Maladies Endocriniennes Rares de la Croissance, Paris, France .

Background: Glycemic variability (GV) can be used to assess glycemic control in diabetes, but there is no clear consensus concerning the methods to use for its assessment. Methodological differences have resulted in differences in the outcome of GV metrics used in research studies, controversies over clinical impact, and an absence of integration into routine care.

Aim: To identify the indicators of GV most meaningful for clinicians, patients, and clinical researchers.

Materials And Methods: Continuous glucose monitoring data were collected during the first 3 months of a pediatric diabetes clinical trial (Start-In!; n = 142). We used principal component analysis (PCA) to analyze weekly averages for 22 parameters relating to GV.

Results: PCA identified five groups of parameters and three components explaining 85.7% of the variance. These components represented the amplitude, direction (hypoglycemia vs. hyperglycemia), and timing (within-day vs. between-days) of glucose excursions.

Conclusions: This study provides elements that could make GV parameters more useful in clinical practice and research. No single parameter was sufficient to represent the complexity of GV, but it was possible to restrict the number of indicators required. The five groups of parameters identified by PCA could facilitate the choice of the most relevant outcomes for GV analysis in pediatric diabetes according to the purpose of the analysis (e.g., exploration of GV associated with hypo- or hyperglycemia, with short- or long-term periodicity, or GV in its entirety).
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http://dx.doi.org/10.1089/dia.2017.0404DOI Listing
June 2018

Increased risk of bone tumors after growth hormone treatment in childhood: A population-based cohort study in France.

Cancer Med 2018 Jun 14. Epub 2018 Jun 14.

Assistance Publique-Hôpitaux de Paris, Biostatistics and Epidemiology Unit, Hôtel Dieu, Paris, France.

The association between growth hormone (GH) treatment and cancer risk has not been thoroughly evaluated and there are questions about any increased risk of bone tumors. We examined cancer risk and especially bone tumor risk in a population-based cohort study of 6874 patients treated with recombinant GH in France for isolated GH deficiency, short stature associated with low birth weight or length or idiopathic short stature. Adult mortality and morbidity data obtained from national databases and from questionnaires. Case ascertainment completeness was estimated with capture-recapture methods. Standardized mortality and incidence ratios were calculated using national reference data. 111 875 person-years of observation were analyzed and patients were followed for an average of 17.4 ± 5.3 years to a mean age of 28.4 ± 6.2 years. For cancer overall, mortality and incidence were not different from expected figures. Five patients developed bone tumors (chondrosarcoma, 1, Ewing sarcoma, 1, osteosarcoma, 3) of whom 3 died (Ewing sarcoma, 1, osteosarcoma, 2), whereas only 1.4 case and 0.6 deaths were expected: standardized mortality ratio, 5.0 and standardized incidence ratio from 3.5 to 3.8 accounting or not accounting for missed cases. Most patients received conventional doses of GH, although one patient with osteosarcoma had received high dose GH (60 μg/kg/d). This study confirms an increased risk of bone tumors but not overall cancer risk in subjects treated with GH in childhood for isolated GH deficiency or childhood short stature. Further work is needed to elucidate the mechanisms involved.
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http://dx.doi.org/10.1002/cam4.1602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6051149PMC
June 2018

Association of maternal nutrition with transient neonatal hyperinsulinism.

PLoS One 2018 3;13(5):e0195383. Epub 2018 May 3.

Service de Diabétologie et Endocrinologie Pédiatrique, Departement de Pédiatrie, et Centre de Reference des Maladies Endocriniennes Rares de la Thyroïde et de l'Hypophyse, Centre Hospitalier Universitaire d'Angers, Angers, France.

Objective: The objective was to determine whether maternal nutritional factors are associated with transient neonatal hyperinsulinism (HI).

Design And Setting: Case control study in 4 French tertiary Obstetrics and Neonatology Departments between 2008 and 2015.

Methods: Sixty-seven mothers of neonates diagnosed with transient hyperinsulinism and 113 mothers of controls were included. The screening for hyperinsulinemic hypoglycemia in neonates was performed because of clinical symptoms suggestive of hypoglycemia or in the presence of conventional risk factors (small-for-gestational-age, prematurity, anoxo-ischemia, hypothermia, macrosomia, gestational diabetes). Hyperinsulinemic hypoglycemia was confirmed in the HI neonates and ruled out in the controls. This allowed for comparing maternal nutrition in cases and controls in a context of similar risk factors. One to 2 mothers of control neonates were included per case, and a food frequency questionnaire was addressed to the mothers between day 5 and day 10 after the birth of their newborn.

Results: Crude odds ratio showed that maternal weight gain, abnormal fetal rate, C-section, gender, consumption of fresh cooked vegetables, fresh fruits and fruit juices, low fat diary products, light fat products, and daily bread were significantly associated with hyperinsulinism. Maternal body mass index, hypertension, gestational diabetes, birth weight percentile, gestational age and 5-minute Apgar score were not related to HI. In a multiple backward logistic regression model, consumption of fresh cooked vegetable ≥1/day (OR = 0.33 [0.14-0.77]) and light-fat products ≥1/week (OR = 0.24 [0.08-0.71]) was protective against hyperinsulinism, whereas gestational weight gain >20 kg (OR = 9.5 [2.0-45.5]) and between 15-20 kg (OR = 4.0 [1.2-14.0]), abnormal fetal heart rate (OR = 4.4 [1.6-12.0]), and C-section (OR = 3.4 [1.3-8.9]) were risk factors.

Conclusions: A diet rich in fresh cooked vegetable and reduced in fat, together with the avoidance of a high gestational weight gain may be protective against transient neonatal hyperinsulinism.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0195383PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933751PMC
August 2018

Growth hormone in combination with leuprorelin in pubertal children with idiopathic short stature.

Endocr Connect 2018 May 18;7(5):708-718. Epub 2018 Apr 18.

Assistance Publique-Hôpitaux de Paris (AP-HP)Hôpital Universitaire Robert-Debré, Department of Pediatric Endocrinology and Diabetology, and Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Paris, France

Objective: There is a scarcity of data from randomised controlled trials on the association of growth hormone (GH) with gonadotrophin-releasing hormone agonists in idiopathic short stature (ISS), although this off-label use is common. We aimed to test whether delaying pubertal progression could increase near-adult height (NAH) in GH-treated patients with ISS.

Methods: Patients with ISS at puberty onset were randomised to GH with leuprorelin (combination,  = 46) or GH alone ( = 45). NAH standard deviation score (SDS) was the primary outcome measure. The French regulatory authority requested premature discontinuation of study treatments after approximately 2.4 years; patients from France were followed for safety.

Results: Mean (s.d.) baseline height SDS was -2.5 (0.5) in both groups, increasing at 2 years to -2.3 (0.6) with combination and -1.8 (0.7) with GH alone. NAH SDS was -1.8 (0.5) with combination ( = 19) and -1.9 (0.8) with GH alone ( = 16). Treatment-emergent adverse events and bone fractures occurred more frequently with combination than GH alone.

Conclusion: Due to premature discontinuation of treatments, statistical comparison of NAH SDS between the two cohorts was not possible. During the first 2-3 years of treatment, patients treated with the combination grew more slowly than those receiving GH alone. However, mean NAH SDS was similar in the two groups. No new GH-related safety concerns were revealed. A potentially deleterious effect of combined treatment on bone fracture incidence was identified.
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http://dx.doi.org/10.1530/EC-18-0137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5952247PMC
May 2018

Can growth hormone treatment improve growth in children with severe growth failure due to anorexia nervosa? A preliminary pilot study.

Endocr Connect 2017 Nov 16;6(8):839-846. Epub 2017 Oct 16.

Assistance Publique-Hôpitaux de ParisHôpital Robert Debré, Service de Psychiatrie de l'Enfant et de l'Adolescent, Centre de Référence des Maladies Endocriniennes de la Croissance et du développement, Paris, France.

Background/aims: Growth failure is a difficult but key aspect of care in children with anorexia nervosa (AN). The effects of hGH therapy have not been studied. The aim was to investigate the effect of hGH treatment on height velocity (HV) in children with AN.

Methods: We carried out a retrospective observational study. Ten girls diagnosed with AN at 10.0 ± 1.9 years, with prolonged severe growth failure (HV < 2.5 cm/year for at least 18 months) at the age of 13.3 ± 1.1 years and delayed puberty after nutritional rehabilitation, were treated with hGH (0.040 mg/kg/day) from a bone age of 10.9 ± 1.7 years until they reached adult height. Height and HV were measured before treatment and at 12-month intervals during treatment.

Results: Mean body mass index SDS remained unchanged, but HV increased significantly, from a median of 1.0 (0.7-2.1) to 7.1 (6.0-9.5) cm/year after one year ( < 0.002) and 5.6 (4.8-6.2) cm/year after two years of treatment. Height SDS increased from -2.2 ± 1.3 to -1.6 ± 1.3 after one year ( < 0.002) and -1.1 ± 1.5 after two years of GH treatment. Adult height (-0.1 ± 1.0 SDS) was close to target height after 3.6 ± 1.4 years of GH treatment. Serum IGF-I levels increased significantly during treatment ( < 0.01). The treatment was well tolerated.

Conclusions: This proof-of-concept study shows that hGH treatment is associated with significant improvements in linear growth in adolescents with AN and severe growth failure. A randomized placebo-controlled trial is required to determine the ultimate impact of GH treatment in patients with this severe, rare condition.
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http://dx.doi.org/10.1530/EC-17-0200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5682412PMC
November 2017

Growth Outcomes After GH Therapy of Patients Given Long-Term Corticosteroids for Juvenile Idiopathic Arthritis.

J Clin Endocrinol Metab 2017 12;102(12):4578-4587

Assistance Publique-Hôpitaux de Paris, Hôpital Robert Debré, Service d'Endocrinologie Diabétologie Pédiatrique, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, France.

Context: Growth hormone (GH) therapy may improve statural growth outcomes in patients with severe juvenile idiopathic arthritis (JIA).

Objectives: To evaluate the effect of GH treatment on adult height and to identify determinants of growth outcomes in JIA.

Design And Patients: Data from 58 patients with JIA, including 53 receiving GH, enrolled in three prospective clinical trials between 1997 and 2002 were analyzed.

Intervention: GH (0.056 mg/kg/d [interquartile range (IQR), 0.050 to 0.062]) for a median duration of 6.5 years (IQR, 4.7 to 7.9 years).

Main Outcome Measures: Factors associated with a favorable growth outcome (adult height - target height ≤ -1.5 standard deviations) were identified by multivariate logistic regression.

Results: Adult height was available for 48 patients 8.6 years after GH initiation (IQR, 6.0 to 10.2 years). Height standard deviation score (SDS) increased from -2.9 (IQR, -4.4 to -1.6) at baseline to -1.7 (IQR, -3.9 to -0.1) in adulthood (P < 0.001). Median adult height was below target height [SDS, -0.2 (IQR, -1.4 to 0.4); P < 0.001]. Corrected adult height SDS was -1.3 (IQR, -3.0 to -0.2). Growth outcome was favorable in 24 (52.2%) patients. Significant independent determinants of growth outcome were age at GH initiation [adjusted odds ratio (aOR), 0.68 per additional year; 95% confidence interval (CI), 0.47 to 0.99], height at GH initiation (aOR, 2.6 per additional SDS; 95% CI, 1.15 to 5.9), and mean C-reactive protein levels during follow up (aOR, 0.51 per additional 10 mg/L; 95% CI, 0.28 to 0.92).

Conclusion: Long-term GH treatment significantly increased growth in patients with JIA but did not fully restore the genetic growth potential. The response showed marked interindividual variability and was weaker in patients with severe inflammation.
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http://dx.doi.org/10.1210/jc.2017-01455DOI Listing
December 2017

A new efficient method to monitor precocious puberty nationwide in France.

Eur J Pediatr 2018 Feb 3;177(2):251-255. Epub 2017 Oct 3.

Department of Pediatric Endocrinology and Diabetology, and Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Robert-Debré, F-75019, Paris, France.

Clinical precocious puberty (PP) is a disease, reputed to be on the increase and suspected to be linked to endocrine disrupting chemicals (EDC) exposure. Population-based epidemiological data are lacking in France and scarce elsewhere. We accessed the feasibility of monitoring PP nationwide in France in this context, using a nationwide existing database, the French National Health Insurance Information System. Here, we present the method we used with a step-by-step approach to build and select the most suitable indicator. We built three indicators reflecting the incidence of idiopathic central precocious puberty (ICPP), the most frequent form of PP, and we compared these indicators according to their strengths and weaknesses with respect to surveillance purposes.

Conclusion: Monitoring ICPP in France proved feasible using a Drug reimbursement indicator. Our method is cost efficient and highly relevant in public health surveillance. Our step-by-step approach proved helpful to achieve this project and could be proposed for assessing the feasibility of monitoring health outcomes of interest using existing data bases. What is known: • Precocious puberty (PP) is suspected to be related to EDC exposure and it is believed to be on the increase in France and in others countries. • Very few epidemiologic data on PP are currently available in the world at the national scale. What is new: • This is the first study describing a method to monitor the most frequent form of PP, idiopathic central PP (ICPP) nationwide in a cost-efficient way, using health insurance databases. • This cost-effective method will allow to estimate and monitor the incidence of ICPP in France and to analyze spatial variations at a very precise scale, which will be very useful to examine the role of environmental exposures, especially to EDCs.
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http://dx.doi.org/10.1007/s00431-017-3012-yDOI Listing
February 2018

Marked geographic patterns in the incidence of idiopathic central precocious puberty: a nationwide study in France.

Eur J Endocrinol 2018 Jan 10;178(1):33-41. Epub 2017 Sep 10.

PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, F-75019 Paris, France.

Objectives: Precocious puberty seems to be increasing but epidemiological data are scarce. Our objective was to improve the epidemiologic knowledge on this disease. We analyzed the national incidence and spatial trends of idiopathic central precocious puberty in France in 2011-2013 in a cross-sectional descriptive study.

Design: We used an indicator based on treatment reimbursements recorded in the national insurance database, in girls under the age of nine years and in boys under the age of 10 years. We considered a time lag of up to one year from the onset of puberty to first drug delivery. We tested four different predictive spatial models at the scale, selecting the model best fitting the data. We carried out semi-structured interviews with qualified hospital teams in five selected regions to investigate spatial differences in medical practices.

Results: The national annual incidence was 2.68 (95% CI: 2.55, 2.81) per 10 000 girls under the age of 9 years and 0.24 (95% CI: 0.21, 0.27) per 10 000 boys under the age of 10 years. Incidence rates conformed to a purely spatial heterogeneity model in girls, consistent between age groups, with a large incidence range. A similar pattern was observed for boys, with peaks in the South West and Center East. Differences in medical practices may have slightly affected incidence locally, but could not entirely explain the marked geographic pattern.

Conclusions: The results suggest that the risk factors are similar for boys and girls and justify further investigations of the role of the environment.
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http://dx.doi.org/10.1530/EJE-17-0379DOI Listing
January 2018

Impact of the underlying etiology of growth hormone deficiency on serum IGF-I SDS levels during GH treatment in children.

Eur J Endocrinol 2017 Sep;177(3):267-276

Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Robert Debré, Service d'Endocrinologie Diabétologie Pédiatrique, Centre de Référence des Maladies Endocriniennes Rares de la Croissance et du développement, Paris, France.

Context: Regular monitoring of serum IGF-I levels during growth hormone (GH) therapy has been recommended, for assessing treatment compliance and safety.

Objective: To investigate serum IGF-I SDS levels during GH treatment in children with GH deficiency, and to identify potential determinants of these levels.

Design, Patients And Methods: This observational cohort study included all patients ( = 308) with childhood-onset non-acquired or acquired GH deficiency (GHD) included in the database of a single academic pediatric care center over a period of 10 years for whom at least one serum IGF-I SDS determination during GH treatment was available. These determinations had to have been carried out centrally, with the same immunoradiometric assay. Serum IGF-I SDS levels were determined as a function of sex, age and pubertal stage, according to our published normative data.

Results: Over a median of 4.0 (2-5.8) years of GH treatment per patient, 995 serum IGF-I SDS determinations were recorded. In addition to BMI SDS, height SDS and GH dose ( < 0.01), etiological group ( < 0.01) had a significant effect on serum IGF-I SDS levels, with patients suffering from acquired GHD having higher serum IGF-I SDS levels than those with non-acquired GHD, whereas sex, age, pubertal stage, treatment duration, hormonal status (isolated GHD (IGHD) vs multiple pituitary hormone deficiency (MPHD)) and initial severity of GHD, had no effect.

Conclusions: These original findings have important clinical implications for long-term management and highlight the need for careful and appropriate monitoring of serum IGF-I SDS and GH dose, particularly in patients with acquired GHD, to prevent the unnecessary impact of potential comorbid conditions.
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http://dx.doi.org/10.1530/EJE-17-0215DOI Listing
September 2017

MANAGEMENT OF ENDOCRINE DISEASE: Arguments for the prolonged use of antithyroid drugs in children with Graves' disease.

Eur J Endocrinol 2017 Aug 5;177(2):R59-R67. Epub 2017 Apr 5.

Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Robert Debré, Service d'Endocrinologie Diabétologie Pédiatrique, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Paris, France.

Graves' disease is an autoimmune disorder. It is the leading cause of hyperthyroidism, but is rare in children. Patients are initially managed with antithyroid drugs (ATDs), such as methimazole/carbimazole. A major disadvantage of treatment with ATD is the high risk of relapse, exceeding 70% of children treated for duration of 2 years, and the potential major side effects of the drug reported in exceptional cases. The major advantage of ATD treatment is that normal homeostasis of the hypothalamus-pituitary-thyroid axis may be restored, with periods of drug treatment followed by freedom from medical intervention achieved in approximately 40-50% of cases after prolonged treatment with ATD, for several years, in recent studies. Alternative ablative treatments such as radioactive iodine and, less frequently and mostly in cases of very high volume goiters or in children under the age of 5 years, thyroidectomy, performed by pediatric surgeons with extensive experience should be proposed in cases of non-compliance, intolerance to medical treatment or relapse after prolonged medical treatment. Ablative treatments are effective against hyperthyroidism, but they require the subsequent administration of levothyroxine throughout the patient's life. This review considers data relating to the prognosis for Graves' disease remission in children and explores the limitations of study designs and results; and the emerging proposal for management through the prolonged use of ATD drugs.
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http://dx.doi.org/10.1530/EJE-16-0938DOI Listing
August 2017