Publications by authors named "Juliane Léger"

132 Publications

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

Abnormal bone mineral density and content in girls with early-onset anorexia nervosa.

J Eat Disord 2021 Jan 10;9(1). Epub 2021 Jan 10.

Child and Adolescent Psychiatry Department, Assistance Publique-Hôpitaux de Paris, Robert Debré University Hospital, Paris, France.

Background: Early-onset anorexia nervosa (EO-AN) represents a significant clinical burden to paediatric and mental health services. The impact of EO-AN on bone mineral abnormalities has not been thoroughly investigated due to inadequate control for pubertal status. In this study, we investigated bone mineral abnormalities in girls with EO-AN regardless of pubertal development stage.

Method: We conducted a cross-sectional study of 67 girls with EO-AN (median age = 12.4 [10.9-13.7 years]) after a median duration of disease of 1.3 [0.6-2.0] years, and 67 healthy age-, sex-, pubertal status- matched control subjects. We compared relevant bone mineral parameters between groups: the total body bone mineral density [TB-BMD], the lumbar spine BMD [LS-BMD], the total body bone mineral content [TB-BMC] and the ratio of the TB-BMC to lean body mass [TB-BMC/LBM].

Results: TB-BMD, TB-BMC, LS-BMD and TB-BMC/LBM were all significantly lower in patients with AN compared to controls. In the EO-AN group, older age, later pubertal stages and higher lean body mass were associated with higher TB-BMC, TB-BMD, and LS-BMD values.

Discussion: Girls with EO-AN displayed deficits in bone mineral content and density after adjustment for pubertal maturation. Age, higher pubertal stage and lean body mass were identified as determinants of bone maturation in the clinical population of patients with EO-AN. Bone health should be promoted in patients, specifically in those with an onset of disorder before 14 years old and with a delayed puberty.
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http://dx.doi.org/10.1186/s40337-020-00365-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798269PMC
January 2021

Pregnancy outcomes in women with preexisting thyroid diseases: a French cohort study.

J Dev Orig Health Dis 2020 Dec 10:1-10. Epub 2020 Dec 10.

Université de Paris, CRESS, INSERM, INRAE, F-75004Paris, France.

Women with thyroid diseases at the beginning of pregnancy may have suboptimal thyroid hormone levels because of potential difficulties in compensating for the physiological thyroid hormone changes occurring in pregnancy. Our objective was to study the association between preexisting thyroid diseases, pregnancy complications, and neonatal anthropometry. In total, 16,395 women from the ELFE French longitudinal birth cohort were included, and 273 declared pre-pregnancy thyroid diseases. Associations were investigated with multivariable regression models, with adjustment for relevant potential confounders. Body mass index (BMI) was additionally adjusted for in a second stage. As compared with other women, women with pre-pregnancy thyroid diseases were more frequently obese (19.6% vs. 9.8%) and had greater odds of gestational diabetes development (odds ratio [OR] = 1.58 [95% confidence interval [CI] 1.08, 2.30]) or had undergone treatment for infertility (OR = 1.57 [95% CI 1.07, 2.31]). After adjustment for BMI, the association with gestational diabetes was no longer significant (OR = 1.27 [95% CI 0.86, 1.88]). After excluding women with another medical history, those with pre-pregnancy thyroid diseases had increased odds of premature rupture of membranes (OR = 1.51 [95% CI 1.01, 2.25]). Children born from mothers with hypothyroidism before conception due to a disease or as a potential side effect of treatment had a smaller head circumference at birth than other children (β = -0.23 [95% CI -0.44, -0.01] cm). In conclusion, pre-pregnancy thyroid diseases were associated with risk of infertility treatment, gestational diabetes, and premature rupture of membranes. The association between history of hypothyroidism and moderate adverse effects on fetal head circumference growth needs replication.
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http://dx.doi.org/10.1017/S2040174420001051DOI Listing
December 2020

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

Clin Endocrinol (Oxf) 2020 Dec 9. Epub 2020 Dec 9.

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
December 2020

Congenital hypothyroidism: a 2020 consensus guidelines update An ENDO-EUROPEAN REFERENCE NETWORK (ERN) initiative endorsed by the European Society for Pediatric Endocrinology and the European Society for Endocrinology.

Thyroid 2020 Dec 3. Epub 2020 Dec 3.

Hôpital Necker Enfants Malades, Pediatric endocrinology and diabetology, Paris, France.

Background An ENDO-ERN initiative was launched which was endorsed by the European Society for Pediatric Endocrinology and the European Society for Endocrinology with 22 participants from the ENDO-ERN and the two societies. The aim was to update the practice guidelines for the diagnosis and management of congenital hypothyroidism (CH). A systematic literature search was conducted to identify key articles on neonatal screening, diagnosis and management of primary and central congenital hypothyroidism. The evidence-based guidelines were graded with the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system, describing both the strength of recommendations and the quality of evidence. In the absence of sufficient evidence, conclusions were based on expert opinion. Summary The recommendations include the various neonatal screening approaches for CH as well as the etiology (also genetics), diagnostics, treatment and prognosis of both primary and central CH. When CH is diagnosed, the expert panel recommends the immediate start of correctly dosed levothyroxine treatment and frequent follow-up including laboratory testing to keep thyroid hormone levels in their target ranges, timely assessment of the need to continue treatment, attention for neurodevelopment and neurosensory functions and, if necessary, consulting other health professionals, and education of the child and family about CH. Harmonisation of diagnostics, treatment and follow-up will optimise patient outcomes. Lastly, all individuals with CH are entitled to a well-planned transition of care from pediatrics to adult medicine. Conclusions This consensus guidelines update should be used to further optimize detection, diagnosis, treatment and follow-up of children with all forms of CH in the light of the most recent evidence. It should be helpful in convincing health authorities of the benefits of neonatal screening for CH. Further epidemiological and experimental studies are needed to understand the increased incidence of this condition.
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http://dx.doi.org/10.1089/thy.2020.0333DOI Listing
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

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

ENDOCRINOLOGY IN THE TIME OF COVID-19: Management of hyperthyroidism and hypothyroidism.

Eur J Endocrinol 2020 Jul;183(1):G33-G39

Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.

This manuscript provides guidance on the management of thyroid dysfunction during the COVID-19 pandemic. Autoimmune thyroid diseases are not linked to increased risks of COVID-19. Uncontrolled thyrotoxicosis may result in more severe complications from SARS-CoV-2 infection, including thyroid storm. The management of patients with a new diagnosis of hyperthyroidism is best undertaken with a block-and-replace regimen due to limited biochemical testing availability. Antithyroid drug (ATD)-induced neutropenia may favour the progression of COVID-19 and symptoms of infection may be confused with SARS-CoV-2 infection. The withdrawal of ATDs and urgent measurement of neutrophils should be considered in case of flu-like manifestations occurring in the initial months of treatment. Urgent surgery or 131-I may be undertaken in selected cases of uncontrolled thyrotoxicosis. Patients with COVID-19 infection may present with conjunctivitis, which could cause diagnostic difficulties in patients with new or existing Graves' ophthalmopathy. Patients who are on replacement treatment with thyroid hormones should ensure they have sufficient supply of medication. The usual advice to increase dosage of levothyroxine during pregnancy should be adhered to. Many newly presenting and previously diagnosed patients with thyroid dysfunction can be managed through virtual telephone or video clinics supported by a dedicated nurse-led service, depending on available facilities.
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http://dx.doi.org/10.1530/EJE-20-0445DOI Listing
July 2020

Endocrinology in the time of COVID-19.

Eur J Endocrinol 2020 Jul;183(1):E1-E2

Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.

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http://dx.doi.org/10.1530/EJE-20-0386DOI Listing
July 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

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

[Epidemiology of congenital hypothyroidism in France: recent data].

Authors:
Juliane Léger

Biol Aujourdhui 2019 5;213(1-2):1-5. Epub 2019 Jul 5.

AP-HP, Hôpital Universitaire Robert Debré, Service d'Endocrinologie Diabétologie Pédiatrique, Centre de Référence des Maladies Endocriniennes Rares de la Croissance et du Développement, Unité d'Epidémiologie Clinique, Université Paris Diderot, Sorbonne Paris Cité, INSERM UMR 1141, DHU Protect, 48 boulevard Sérurier, 75019 Paris, France.

Congenital hypothyroidism (CH) is the leading cause of preventable mental retardation. It is mainly due to thyroid dysgenesis or dyshormonogenesis with normally located gland, and detected at birth in developed countries, by mass biochemical screening of newborns. An increase in the incidence of congenital hypothyroidism with a normally located gland has been reported worldwide over the last three decades. The etiology of CH with a normally located gland remains elusive and the factors driving its clinical diversity are largely unknown. A role for known dyshormonogenesis-associated genetic variants or TSH receptor gene variants is well-known, but the possible effects of environmental agents toxic to the fetal and neonatal thyroid gland are currently being investigated.
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http://dx.doi.org/10.1051/jbio/2019005DOI Listing
January 2020

X chromosome gene dosage as a determinant of congenital malformations and of age-related comorbidity risk in patients with Turner syndrome, from childhood to early adulthood.

Eur J Endocrinol 2019 06;180(6):397-406

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

Objective Turner Syndrome is associated with several phenotypic conditions associated with a higher risk of subsequent comorbidity. We aimed to evaluate the prevalence of congenital malformations and the occurrence of age-related comorbid conditions and to determine whether the frequencies of congenital and acquired conditions depend on X chromosome gene dosage, as a function of karyotype subgroup. Design and methods This national retrospective observational cohort study includes 1501 patients. We evaluated the prevalence of congenital malformations and the cumulative incidence of subsequent specific comorbidities at five-year intervals, from the ages of 10 to 30 years, with stratification by karyotype subgroup: 45,X (n = 549), 45,X/46,isoXq (n = 280), 46,X,r(X)/46,XX (n = 106), 45,X/46,XX (n = 221), presence of Y (n = 87). Results Median age was 9.4 (3.7-13.7) years at first evaluation and 16.8 (11.2-21.4) years at last evaluation. Congenital heart (18.9%) malformations were more frequent in 45,X patients, and congenital renal (17.2%) malformations were more frequent in 45,X, 45,X/46,isoXq and 46,X,r(X)/46,XX patients than in those with 45,X/46,XX mosaicism or a Y chromosome (P < 0.0001). The cumulative incidence of subsequent acquired conditions, such as thyroid disease, hearing loss, overweight/obesity, dyslipidemia and, to a lesser extent, celiac disease, glucose intolerance/type 2 diabetes, hypertension and liver dysfunction increased with age, but less markedly for patients with mosaicism than for those with other karyotypes. Patients with a ring chromosome were more prone to metabolic disorders. Conclusion These data suggest that X gene chromosome dosage, particularly for Xp genes, contributes to the risk of developing comorbidities.
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http://dx.doi.org/10.1530/EJE-18-0878DOI Listing
June 2019

Medication in AN: A Multidisciplinary Overview of Meta-Analyses and Systematic Reviews.

J Clin Med 2019 Feb 25;8(2). Epub 2019 Feb 25.

French Federation Anorexia Bulimia (FFAB), 75014 Paris, France.

Drugs are widely prescribed for anorexia nervosa in the nutritional, somatic, and psychiatric fields. There is no systematic overview in the literature, which simultaneously covers all these types of medication. The main aims of this paper are (1) to offer clinicians an overview of the evidence-based data in the literature concerning the medication (psychotropic drugs and medication for somatic and nutritional complications) in the field of anorexia nervosa since the 1960s, (2) to draw practical conclusions for everyday practise and future research. Searches were performed on three online databases, namely MEDLINE, Epistemonikos and Web of Science. Papers published between September 2011 and January 2019 were considered. Evidence-based data were identified from meta-analyses, if there were none, from systematic reviews, and otherwise from trials (randomized or if not open-label studies). Evidence-based results are scarce. No psychotropic medication has proved efficacious in terms of weight gain, and there is only weak data suggesting it can alleviate certain psychiatric symptoms. Concerning nutritional and somatic conditions, while there is no specific, approved medication, it seems essential not to neglect the interest of innovative therapeutic strategies to treat multi-organic comorbidities. In the final section we discuss how to use these medications in the overall approach to the treatment of anorexia nervosa.
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http://dx.doi.org/10.3390/jcm8020278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406645PMC
February 2019

Growth impairment and limited range of joint motion in children should raise suspicion of an attenuated form of mucopolysaccharidosis: expert opinion.

Eur J Pediatr 2019 Apr 11;178(4):593-603. Epub 2019 Feb 11.

Groupe de Pédiatrie Générale - Société Française de Pédiatrie, Boulogne-Billancourt, Department of Pediatrics and Pediatric Emergency, Ambroise-Paré Hospital, Boulogne-Billancourt, France.

Growth impairment together with bone and joint involvement is common to most patients with mucopolysaccharidosis (MPS) disorders. The genetic basis for these metabolic disorders involves various enzyme deficiencies responsible for the catabolism of glycosaminoglycans (GAGs). The incomplete degradation and subsequent accumulation of GAGs result in progressive tissue damage throughout the body. Bone ossification is particularly affected, with the consequent onset of dysostosis multiplex which is the underlying cause of short stature. Joint manifestations, whether joint contractures (MPS I, II, VI, VII) or hyperlaxity (MPS IV), affect fine motor skills and quality of life. Subtle decreases in growth velocity can begin as early as 2-4 years of age. Pediatricians are in the front line to recognize or suspect MPS. However, given the rarity of the disorders and variable ages of symptom onset depending on disease severity, recognition and diagnostic delays remain a challenge, especially for the attenuated forms. Prompt diagnosis and treatment can prevent irreversible disease outcomes.Conclusion: We present a diagnostic algorithm based on growth velocity decline and bone and joint involvement designed to help pediatricians recognize early manifestations of attenuated forms of MPS. We illustrate the paper with examples of abnormal growth curves and subtle radiographic nuances. What is Known: • As mucopolysaccharidoses (MPSs) are rare genetic disorders infrequently seen in clinical practice, there can be a lag between symptom onset and diagnosis, especially of attenuated forms of the disease. • This highlights the need for increased disease awareness to recognize early clinical signs and subsequently initiate early treatment to improve outcomes (normal height potential) and possibly prevent or delay the development of irreversible disease manifestations. What is New: • Growth impairment co-presenting with limited range of joint motion and radiographic anomalies in children should raise suspicions of possible attenuated MPS (AMPS). • Experts present a diagnostic algorithm with detailed focus on the decline in growth velocity, delayed puberty and limitation in joint mobility seen in children with AMPS, to shorten time-to-diagnosis and treatment and potentially improve patient outcome.
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http://dx.doi.org/10.1007/s00431-019-03330-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438949PMC
April 2019

Refeeding in anorexia nervosa.

Eur J Pediatr 2019 Mar 27;178(3):413-422. Epub 2018 Nov 27.

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

Refeeding in anorexia nervosa is a collaborative enterprise involving multidisciplinary care plans, but clinicians currently lack guidance, as treatment guidelines are based largely on clinical confidence rather than more robust evidence. It seems crucial to identify reproducible approaches to refeeding that simultaneously maximize weight recovery and minimize the associated risks, in addition to improving long-term weight and cognitive and behavioral recovery and reducing relapse rates. We discuss here various approaches to refeeding, including, among others, where, by which route, how rapidly patients are best refed, and ways of choosing between them, taking into account the precautions or the potential effects of medication or of psychological care, to define better care plans for use in clinical practice.Conclusion: The importance of early weight gain for long-term recovery has been demonstrated by several studies in both outpatient and inpatient setting. Recent studies have also provided evidence to support a switch in current care practices for refeeding from a conservative approach to higher calorie refeeding. Finally, the risks of undernutrition/"underfeeding syndrome" and a maintenance of weight suppression are now better identified. Greater caution should still be applied for more severely malnourished < 70% average body weight and/or chronically ill, adult patients. What is Known: • Refeeding is a central part of the treatment in AN and should be a multidisciplinary and collaborative enterprise, together with nutritional rehabilitation and psychological support, but there are no clear guidelines on the management of refeeding in clinical practice. • The risk of a refeeding syndrome is well known and well managed in severely malnourished patients ("conservative approaches"). What is New: • There is evidence that early weight restoration has an impact on outcome, justifying an aggressive approach to refeeding in the early stages of the illness. • The risks of "underfeeding syndrome" and of a maintenance of weight suppression are now better identified and there is sufficient evidence to support a switch in current care practices for refeeding from a conservative approach to higher calorie refeeding. Graphical abstract.
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http://dx.doi.org/10.1007/s00431-018-3295-7DOI Listing
March 2019

Dysregulated glucose homeostasis in congenital central hypoventilation syndrome.

J Pediatr Endocrinol Metab 2018 Dec;31(12):1325-1333

Department of Endocrinology and Diabetes, Lady Cilento Children's Hospital, South Brisbane, Queensland, Australia.

Background Congenital central hypoventilation syndrome (CCHS) is a rare disorder of autonomic control. A hypoglycaemic seizure in a 4-year-old girl with CCHS led to a more detailed examination of glycaemic control in a cohort of children with CCHS. Methods We conducted an observational cohort study of glucose homeostasis in seven children (3 months to 12 years) with genetically confirmed CCHS using a combination of continuous glucose monitoring (CGM), fasting studies and oral glucose tolerance test (OGTT). CGM was used to compare the effect of diazoxide and dietary intervention in the index patient. Results Hypoglycaemia was not elicited by fasting in any of the patients. Increased postprandial glycaemic variability was evident in all patients using CGM, with seven of seven patients demonstrating initial postprandial hyperglycaemia (plasma-glucose concentration >7.8 mmol/L), followed by asymptomatic hypoglycaemia (plasma-glucose concentration ≤2.8 mmol/L) in two of seven patients that was also demonstrated on OGTT. Both diazoxide and low Glycaemic Index (GI) dietary intervention reduced the proportion of CGM readings <4 mmol/L; however, diazoxide also increased the proportion of readings in the hyperglycaemic range. Conclusions Glucose variability associated with autonomic dysfunction may be unrecognised in CCHS, particularly in children with more severe phenotypes. This report highlights the occurrence of hyperglycaemia as well as hypoglycaemia in CCHS. Given the challenges of recognising hypoglycaemia based on clinical symptomatology, the use of CGM may facilitate its identification allowing appropriate management. The observed normoglycaemia during fasting combined with increased postprandial plasma blood glucose level (BGL) variability is more consistent with dumping syndrome than persistent hyperinsulinism. Dietary modifications therefore may be more effective than diazoxide in managing hypoglycaemia.
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http://dx.doi.org/10.1515/jpem-2018-0086DOI Listing
December 2018

TUBB1 mutations cause thyroid dysgenesis associated with abnormal platelet physiology.

EMBO Mol Med 2018 12;10(12)

INSERM U1016, Faculté de Médecine, Cochin Institute, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

The genetic causes of congenital hypothyroidism due to thyroid dysgenesis (TD) remain largely unknown. We identified three novel gene mutations that co-segregated with TD in three distinct families leading to 1.1% of mutations in TD study cohort. (Tubulin, Beta 1 Class VI) encodes for a member of the β-tubulin protein family. gene is expressed in the developing and adult thyroid in humans and mice. All three mutations lead to non-functional α/β-tubulin dimers that cannot be incorporated into microtubules. In mice, knock-out disrupted microtubule integrity by preventing β1-tubulin incorporation and impaired thyroid migration and thyroid hormone secretion. In addition, mutations caused the formation of macroplatelets and hyperaggregation of human platelets after stimulation by low doses of agonists. Our data highlight unexpected roles for β1-tubulin in thyroid development and in platelet physiology. Finally, these findings expand the spectrum of the rare paediatric diseases related to mutations in tubulin-coding genes and provide new insights into the genetic background and mechanisms involved in congenital hypothyroidism and thyroid dysgenesis.
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http://dx.doi.org/10.15252/emmm.201809569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284387PMC
December 2018

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

Graves' disease in children.

Ann Endocrinol (Paris) 2018 Dec 16;79(6):647-655. Epub 2018 Aug 16.

Department of Pediatric Endocrinology and Diabetology and Reference Center for Rare Diseases of Thyroid and Hormone Receptivity, University hospital of Angers, 4, rue Larrey, 49933 Angers cedex 9, France. Electronic address:

R1 The diagnosis of Graves' disease in children is based on detecting a suppression of serum TSH concentrations and the presence of anti-TSH receptor antibodies. 1/+++. R2 Thyroid ultrasound is unnecessary for diagnosis, but can be useful for assessing the size and homogeneity of the goiter. 2/+. R3. Thyroid scintigraphy is not required for the diagnosis of Graves' disease. 1/+++. R4. The measurement of T4L and T3L levels is not necessary for the diagnosis of Graves' disease in children but can be useful for the management and assessment of prognosis. 1/++. R5. In the absence of TSH receptor autoantibodies, the possibility of genetically inherited hyperthyroidism must be considered. 1/++. R6. Drug therapy is the primary line of treatment for children and consists of imidazole, carbimazole or thiamazole, with an initial dosage of 0.4 to 0.8mg/kg/day (0.3 to 0.6mg/kg/day for thiamazole) depending on the initial severity, up to maximum of 30mg. 1/++. R7. Propylthiouracil is contraindicated for children with Grave's disease. 1/+++. R8. Before starting treatment, it may be useful to perform a CBC in order to assess the degree of neutropenia caused by hyperthyroidism. It is not necessary to perform systematic CBCs during follow-up. 2/+. R9. An emergency CBC should be performed if symptoms include fever or angina. If neutrophil counts are <1000/mm, synthetic antithyroid therapy should be discontinued or decreased and may be permanently contraindicated in severe (<500) and persistent neutropenia. Otherwise treatment may be resumed. 1/++. R10. Transaminases levels should be measured before initiating treatment. Systematic monitoring of liver function is not consensually validated. 2/+. R11. In cases of jaundice, digestive disorders or pruritus, measuring liver enzymes (AST, ALT), total and conjugated bilirubin and alkaline phosphatases is indicated. 1/++. R12. Patients and parents should be informed of the possible side effects of antithyroid agents. 1/+. R13. Therapeutic education of parents and children is important in ensuring the best possible treatment compliance. 2/++. R14. Given the specificities involved in the treatment of Graves' disease in children, medical care should be provided by a specialist accustomed to treating endocrinopathies in pediatric patients. 2/+. R15. Depending on patient age, the severity of the disease at diagnosis and the persistence of anti-TSH receptor antibodies, the initial course of treatment must take place over an extended period of 3 to 6 years. R16.The anticipated success rates of medical treatment (50% of patients in remission following several years of treatment) should be explained to the family and the child. The possibility that radical treatment may be required in case of failure or intolerance of medical treatment should also be discussed. 1/++. R17.In females with Graves' disease, it is important to explain that they must undergo an assessment by an endocrinologist before planning future pregnancies, from the start of pregnancy and during the course of pregnancy. This is true in all female patients, even those in remission after medical treatment, or those who have undergone radical treatment. R18.Indications for a radical treatment can arise in cases of: 1/+: contraindication to antithyroid agents; poorly controlled hyperthyroidism due to lack of compliance; relapse despite prolonged medical treatment; a request made by the family and child for personal reasons. R19.Surgery is the radical method of treatment used in children under 5 years of age, or in cases of very large, nodular, or compressive goiters. 2/++. R20. The surgeon's experience in dealing with thyroidectomies in children is likely to be the most significant determining factor in limiting the morbidity of the procedure (alongside any collaboration between a pediatric surgeon and an adult surgeon). 1/++. R21 When radical treatment is indicated, I-131 treatment may be discussed after 5 years (but more often after puberty), if the goiter is not too large. Experience from monitoring Graves' disease in North American children is reassuring. 1/++.
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http://dx.doi.org/10.1016/j.ando.2018.08.001DOI Listing
December 2018

Algorithms to Define Abnormal Growth in Children: External Validation and Head-To-Head Comparison.

J Clin Endocrinol Metab 2019 02;104(2):241-249

INSERM, UMR1153 Epidemiology and Biostatistics Sorbonne Paris Cité Center, Early Origins of the Child's Health and Development Team, Paris Descartes University, Villejuif, France.

Background: Growth monitoring of apparently healthy children aims at early detection of serious conditions by use of both clinical expertise and algorithms that define abnormal growth. The seven existing algorithms provide contradictory definitions of growth abnormality and have a low level of validation.

Objective: An external validation study with head-to-head comparison of the seven algorithms combined with study of the impact of use of the World Health Organization (WHO) vs national growth charts on algorithm performance.

Design: With a case-referent approach, we retrospectively applied all algorithms to growth data for children with Turner syndrome, GH deficiency, or celiac disease (n = 341) as well as apparently healthy children (n = 3406). Sensitivity, specificity, and theoretical reduction in time to diagnosis for each algorithm were calculated for each condition by using the WHO or national growth charts.

Results: Among the two algorithms with high specificity (>98%), the Grote clinical decision rule had higher sensitivity than the Coventry consensus (4.6% to 54% vs 0% to 8.9%, P < 0.05) and offered better theoretical reduction in time to diagnosis (median: 0.0 to 0.9 years vs 0 years, P < 0.05). Sensitivity values were significantly higher with the WHO than national growth charts at the expense of specificity.

Conclusion: The Grote clinical decision rule had the best performance for early detection of the three studied diseases, but its limited potential for reducing time to diagnosis suggests the need for better-performing algorithms based on appropriate growth charts.
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http://dx.doi.org/10.1210/jc.2018-00723DOI Listing
February 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

Epidemiology of Childhood Hyperthyroidism in France: A Nationwide Population-Based Study.

J Clin Endocrinol Metab 2018 08;103(8):2980-2987

Department of Pediatric Endocrinology and Diabetes, Reference Centre for Endocrine Growth and Development Diseases, Hôpital Universitaire Robert Debré, Assistance Publique-Hôpitaux de Paris, Paris, France.

Context: Hyperthyroidism affects all age groups, but epidemiological data for children are scarce.

Objective: To perform a nationwide epidemiological survey of hyperthyroidism in children and adolescents.

Design: A cross-sectional descriptive study.

Setting: Identification of entries corresponding to reimbursements for antithyroid drugs in the French national insurance database.

Participants: All cases of childhood hyperthyroidism (6 months to 17 years of age) in 2015.

Main Outcome Measures: National incidence rate estimated with a nonlinear Poisson model and spatial distribution of cases.

Results: A total of 670 cases of childhood hyperthyroidism were identified. Twenty patients (3%) had associated autoimmune or genetic disease, with type 1 diabetes and Down syndrome the most frequent. The annual incidence for 2015 was 4.58/100,000 person-years (95% CI 3.00 to 6.99/100,000). Incidence increased with age, in both sexes. This increase accelerated after the age of 8 in girls and 10 in boys and was stronger in girls. About 10% of patients were affected before the age of 5 years (sex ratio 1.43). There was an interaction between age and sex, the effect of being female increasing with age: girls were 3.2 times more likely to be affected than boys in the 10 to 14 years age group and 5.7 times more likely to be affected in the 15 to 17 years age group. No conclusions about spatial pattern emerged.

Conclusion: These findings shed light on the incidence of hyperthyroidism and the impact of sex on this incidence during childhood and adolescence. The observed incidence was higher than expected from the results published for earlier studies in Northern European countries.
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http://dx.doi.org/10.1210/jc.2018-00273DOI Listing
August 2018

Early postnatal growth and neurodevelopment in children born moderately preterm or small for gestational age at term: A systematic review.

Paediatr Perinat Epidemiol 2018 05 25;32(3):268-280. Epub 2018 Apr 25.

Early Determinants of Children's Health and Development Team (ORCHAD), Inserm UMR1153 Epidemiology and Biostatistics Sorbonne Paris Cité Center (CRESS), Villejuif, France.

Background: Clinicians' interest in the long-term effects of early postnatal growth (EPG) is growing. There is compelling evidence linking rapid EPG with later cardiovascular risk, but its neurodevelopmental benefits still remain hypothetical in individuals born moderately preterm (MP) or small for gestational at term (SGAT).

Methods: The objective was to perform a systematic review of the relationship between EPG before age 3 years and neurodevelopmental outcome for individuals born MP (32-36 weeks' gestational age) or SGAT. Following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, 3 independent investigators searched for articles published on this topic in the Web of Science, EMBASE and PubMed from database inception to July 1, 2017. A detailed quality scale was used to evaluate articles.

Results: We selected 19 articles relying on 12 distinct study populations; 7 articles from 3 study populations were considered at moderate or high quality. The lack of standardisation of growth analysis methods prevented performing a meta-analysis. Overall, EPG was positively associated with neurodevelopmental outcome, especially Intelligence Quotient (IQ) when available. In this relationship, the first 6 months of life might be a critical period. Analysis of the few articles investigating the shape of the relationships revealed a non-linear association, with a plateau for IQ with higher weight gain, which suggests a possible ceiling effect.

Conclusions: A positive association was generally found between EPG and neurodevelopmental outcome for individuals born MP or SGAT. Strategies for future epidemiological studies are suggested to improve the characterisation of this relationship.
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http://dx.doi.org/10.1111/ppe.12468DOI Listing
May 2018

Developmental milestones at one year for the offspring of mothers with congenital hypothyroidism: a population-based study

Eur J Endocrinol 2018 05 2;178(5):471-480. Epub 2018 Mar 2.

INSERM, UMR1153 Epidemiology and Biostatistics Sorbonne Paris Cité Center, Early Origin of Child Health and Development Team (ORCHAD), Paris, France.

Objective: Maternal thyroid dysfunction during pregnancy is associated with neurodevelopmental impairment in the offspring. No data are currently available for the offspring of patients treated early for congenital hypothyroidism (CH). The aim of this study was to investigate motor and language milestones at one year of age in a population-based registry of children born to young women with CH.

Design And Methods: We assessed 110 children born to mothers with CH, and 1367 children from the EDEN French population-based birth cohort study prospectively, at the age of one year, with identical questionnaires. Outcomes were assessed in terms of scores for childhood developmental milestones relating to mobility, motor coordination, communication, motricity and language skills.

Results: After adjustment for confounding factors, children born to mothers with CH were found to have a higher risk of poor motor coordination than those of the EDEN cohort (OR: 4.18, 95% CI: 2.52-6.93). No differences were identified for the other four domains investigated. Children born to mothers with gestational diabetes have a higher risk of low motor coordination score than their peers (OR: 2.10, 95% CI: 1.21-3.66). Children born to mothers with TSH ≥ 10 IU/L during the first six months of pregnancy were more likely to have low motricity or communication skills scores than those born to mothers with lower TSH concentrations (56% vs 21% for each score,  < 0.04).

Conclusions: Maternal CH may have slight adverse effects on some developmental milestones in the child at one year of age, particularly for children born to mothers with uncontrolled hypothyroidism. However, it remains unclear whether these adverse effects modify subsequent neurodevelopment.
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http://dx.doi.org/10.1530/EJE-17-0855DOI Listing
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

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