[Show abstract][Hide abstract] ABSTRACT: This study was designed to estimate the percentage of growth hormone (GH)-treated children born small for gestational age (SGA), with serum IGF-1 >2 SDS before and after GH dose adaptation.
SGA boys aged 4-9 and girls aged 4-7 with a height <-2 SDS and an annual growth rate below the mean received a subcutaneous GH dose of 57 μg/kg/day for 2 years. The GH dose was to be decreased by 30% in children with serum IGF-1 >2 SDS at 12 months and on the previous sample. The GH dose could be reduced a second time to 35 μg/kg·day. IGF-1 and IGFBP-3 dosages were centralized.
Among the 49 (21 boys) children included in the study, 8 (16.3%) had an IGF-1 >2 SDS consecutively at 9 and 12 months (95% CI 7.3, 29.7). The GH dose was decreased in 6/8 children. However, IGF-1 levels were elevated at several nonconsecutive determinations in 45% (95% CI 28.4, 56.6) of the patients.
A high IGF-1 level is observed in 45% of the GH SGA-treated children with a relatively high dose of GH. A 30% reduction in the GH dose causes a decrease in IGF-1 below 2 SDS in most children.
Hormone Research in Paediatrics 12/2011; 76(6):419-27. DOI:10.1159/000334651 · 1.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Screening programs resulting in the early treatment of patients with congenital hypothyroidism (CH) have successfully improved neurodevelopmental outcome, but little is known about long-term health.
The aim of the study was to assess health status, and socioeconomic attainment, for a population-based registry of young adult patients.
All 1748 eligible patients diagnosed during the first decade after the introduction of neonatal screening in France were invited to participate in this study at a median age of 23.4 yr. Completed questionnaires were obtained from 1202 of the selected patients. The comparison group included 5817 subjects from the last French Decennial Health Survey.
Health indicators including medical conditions, hearing and visual status, sociodemographic characteristics, and quality of life were measured.
Patients with CH were significantly more likely than their peers to report associated chronic diseases (5.7 vs. 2.9%), hearing impairment (9.5 vs. 2.5%), visual problems (55.4 vs. 47.9%), and being overweight with a body mass index of at least 25 kg/m(2) (22.8 vs. 15.7%) (P < 0.0001). Furthermore, fewer patients attained the highest socioeconomic category (14.6 vs. 23.1%) and were in full-time employment (39.9 vs. 44.8%) (P < 0.0001). They were more likely to still be living with their parents and had a lower health-related quality of life than their healthy peers, particularly for mental dimensions, with a mean difference for the mental summary component of 0.35 SD score (P < 0.0001). CH severity at diagnosis, treatment adequacy, and the presence of other chronic health conditions were the main determinants of educational achievement and health-related quality of life scores.
These findings highlight the need for careful monitoring of neurosensory functioning, weight, and long-term treatment adequacy throughout childhood and adulthood.
The Journal of Clinical Endocrinology and Metabolism 03/2011; 96(6):1771-82. DOI:10.1210/jc.2010-2315 · 6.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: L’hypothyroïdie congénitale (HC) (1/3500) est due dans la majorité des cas à une dysgénésie thyroïdienne (athyréose ou ectopie). Lorsque la thyroïde est en place (GP), les dyshormonogenèses n’expliquent que 1/3 des cas.
L’objectif de l’étude a été d’analyser l’étiologie et l’évolution des HC avec GP. Sujets : 131 enfants dépistés en Ile de France entre 2005 et 2008 ont été étudiés.
Résultats : Une scintigraphie a été effectuée chez 84 enfants (64 %) et une dyshormonogenèse a été diagnostiqué dans 48 cas (37 %). 4 cas de faux positifs et 20 cas d’HC transitoire d’étiologie « classique » (prématurité, trouble iodé, anticorps antithyroïdiens et/ou PTU chez la mère) ont été observés. Lorsque l’étiologie était indéterminée et un traitement substitutif instauré (n = 44), un arrêt de traitement a été tenté chez 15 enfants (âge moyen 17 mois [2-46]) sans récidive de l’hypothyroïdie chez 13 d’entre eux (86 %). De même, 3 enfants avec dyshormonogenèse ont arrêté la L-Thyroxine avec succès.
Au total, dans les cas d’HC avec GP d’étiologie indéterminée, un arrêt de traitement substitutif a été possible dans 86 % des cas testés et devrait donc être proposé plus systématiquement. Reste à définir les critères cliniques, biologiques et/ou radiologiques pour permettre des recommandations consensuelles.
Archives de Pédiatrie 06/2010; 17(6):5-5. DOI:10.1016/S0929-693X(10)70233-5 · 0.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ante- and post-hypophysis are the two constituents of the hypophysis. The ante-hypophysis synthesizes and secretes mainly the growth hormone, thyrotropin, prolactin, adrenocorticotropic hormones and the gonadotrophins. The vasopressin and oxytocin hormones are secreted by the post-hypophysis. The hypophysis development and differentiation are controlled by a chain of different factors that involve numerous signalisation genes from adjacent structures, in addition to specific transcription factors, to date insufficiently known. The regulation and mode of action of the various hormones are now well identified. Activating and inhibiting hormones synthesized in the hypothalamus regulate the functioning of ante-hypophysis cells. They act through specific cellular receptors. In children, hypothalamus-hypophysis hypofunction is far more frequently observed than hyperfunction. Hypopituitarisms are serious diseases which, if untreated, may have irreversible consequences such as severe nanism in case of somatotropic insufficiency, mental retardation in case of thyrotropic insufficiency, lack of puberty development and sterility in case of gonadotropic insufficiency, and even death in case of corticotropic insufficiency. The diagnosis of hypophysis insufficiency is based on clinical data, and results of functional investigations, and brain magnetic resonance imaging. Treatments are substitutive, given for life, and concerned patients necessitate lifelong medical management. Hypophysis insufficiency may be either isolated or multiple, either acquired (mainly in relation with a tumoral or infiltrative process in the hypothalamus-hypophysis area), or congenital. Various types of human congenital insufficiency (isolated or combined) due to a genetic cause have been described these last years. However, the molecular mechanisms that produce the major part of genetic hypopituitarisms remain to be elucidated.
[Show abstract][Hide abstract] ABSTRACT: Obesity and type 2 diabetes (T2DM) in children and adolescents are increasing in developed and developing countries. We have every reason to fear, already, a parallel epidemic in France. We discussed the phenotypic characterization of diabetes in children and adolescent (type 1 diabetes, MODY mainly MODY3, and true T2DM), which have clinical and therapeutic implications, a distinction not always easy. Familial history of T2DM, initial BMI, body weight loss, severity of hyperglycemia and a ketonuria are often not sufficient to determine the etiologic diagnosis. The search for specific islet-cell autoantibodies and for MODY3, are often necessary for classification, and to guide therapeutic strategies. This review presents preliminary French data, based on the comparison of the annual frequency of T2DM between two periods (2001-2003 vs. 1993-1998), in our pediatric diabetes department. A significant increase of T2DM has been found: 14/271 new cases of diabetes (age <16 yrs) in 2001-2003 were T2DM vs. 8/370 in 1993-98 (i.e. 5.2% vs. 2.2%). By contrast with other countries, most of these young T2DM patients are Caucasians. The treatment allows a good glycemic control when diet and physical advices are well followed, and supported by the pediatric team. A monotherapy with metformin is usually sufficient for treating these patients after a short and transient insulin therapy.
Médecine des Maladies Métaboliques 03/2009; 3(2). DOI:10.1016/S1957-2557(09)71644-X
[Show abstract][Hide abstract] ABSTRACT: Low birth weight remains a major cause of morbidity and mortality in early infancy and childhood. It is associated with an increased risk of health problems later in life, particularly coronary heart disease and stroke. A meeting was convened to identify the key health issues facing a child born small for gestational age (SGA) and to propose management strategies.
There were 42 participants chosen for their expertise in obstetrics, peri- and neonatal medicine, pediatrics, pediatric and adult endocrinology, epidemiology, and pharmacology.
Written materials were exchanged, reviewed, revised, and then made available to all. This formed the basis for discussions at the meeting. Where published data were not available or adequate, discussion was based on expert clinical opinions.
Each set of questions was considered by all and then discussed in plenary sessions with consensus and unresolved issues identified. The consensus statement was prepared in plenary sessions and then edited by the group chairs and shared with all participants.
The diagnosis of SGA should be based on accurate anthropometry at birth including weight, length, and head circumference. We recommend early surveillance in a growth clinic for those without catch-up. Early neurodevelopment evaluation and interventions are warranted in at-risk children. Endocrine and metabolic disturbances in the SGA child are recognized but infrequent. For the 10% who lack catch-up, GH treatment can increase linear growth. Early intervention with GH for those with severe growth retardation (height sd score, <-2.5; age, 2-4 yr) should be considered at a dose of 35-70 microg/kg x d. Long-term surveillance of treated patients is essential. The associations at a population level between low birth weight, including SGA, and coronary heart disease and stroke in later life are recognized, but there is inadequate evidence to recommend routine health surveillance of all adults born SGA outside of normal clinical practice.
[Show abstract][Hide abstract] ABSTRACT: Aims To examine incidence and trends of Type 1 diabetes worldwide for the period 1990-1999. Methods The incidence of Type 1 diabetes (per 100 000/year) was analysed in children aged <= 14 years from 114 populations in 112 centres in 57 countries. Trends in the incidence of Type 1 diabetes were analysed by fitting Poisson regression models to the dataset. Results A total of 43 013 cases were diagnosed in the study populations of 84 million children. The age-adjusted incidence of Type 1 diabetes among 112 centres (114 populations) varied from 0.1 per 100 000/year in China and Venezuela to 40.9 per 100 000/year in Finland. The average annual increase in incidence calculated from 103 centres was 2.8% (95% CI 2.4-3.2%). During the years 1990-1994, this increase was 2.4% (95% CI 1.3-3.4%) and during the second study period of 1995-1999 it was slightly higher at 3.4% (95% CI 2.7-4.3%). The trends estimated for continents showed statistically significant increases all over the world (4.0% in Asia, 3.2% in Europe and 5.3% in North America), except in Central America and the West Indies where the trend was a decrease of 3.6%. Only among the European populations did the trend in incidence diminish with age. Conclusions The rising incidence of Type 1 diabetes globally suggests the need for continuous monitoring of incidence by using standardized methods in order to plan or assess prevention strategies.
Diabetic Medicine 08/2006; 23(8):857-866. DOI:10.1111/j.1464-5491.2006.01925.x · 3.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We have previously shown that the human developing pancreas, as a tissue under construction and remodeling, is composed of epithelial ducts and differentiated endocrine cells surrounded by mesenchyme. The physiologic importance of resident tissue leukocytes, expected to enter through the mesenchyme in remodeling functions, prompted us to investigate human developing pancreases for the presence of leukocyte lineages and for expression of cytokines and receptors involved in their recruitment and differentiation. Immunohistochemistry studies were performed on 69 human, paraffin-embedded pancreases at 6-12 weeks of development (WD). Cytokines and receptor transcripts were monitored by reverse transcription (RT)-PCR, by immunohistochemistry when antibodies were available or by in situ hybridization (ISH). We show that numerous cells expressing CD45RA, HLADR and CD68 antigens are cellular components of the mesenchyme of all the pancreases at 6-12 WD. So-called constitutive chemokines (SLC (CCL19), stromal-derived factor 1 (SDF1) (CXCL12)) and a macrophage-specific growth/survival factor, colony-stimulating factor 1 (CSF1), were detected in epithelial duct cells. Both epithelial and mesenchymal cells expressed chemokine receptors, suggesting a role in leukocyte recruitment and possibly in early pancreatic development. In conclusion, we demonstrated the presence of CD45RA resident leukocyte-derived lineages, mostly macrophages, in the early human pancreatic mesenchyme. These cells may have migrated in the tissue through the vascular system, attracted by constitutively expressed chemokines, and locally surviving through CSF1 signaling. The role of macrophages in epithelium/mesenchyme interaction-mediated pancreatic development remains to be demonstrated.
Journal of Endocrinology 04/2006; 188(3):467-80. DOI:10.1677/joe.1.06225 · 3.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Treatment of short children born small for gestational age SGA with recombinant human growth hormone r-hGH increases growth velocity during childhood. As in other indications, the growth velocity in these patients is more marked during the first year of treatment and then decreases. This study was undertaken to evaluate the efficacy of different r-hGH treatment schedules (67 microg/kg/day in a discontinuous or continuous regimen) during the second year of r-hGH treatment by comparing height velocity changes and total gain of height over a 4-year period.
58 growth-retarded SGA children aged 2-5 years were randomized to a TOTO regimen (4 years alternating treatment (T) and observation (O), n = 30) or a TTOO regimen (2 years' treatment, followed by 2 years' observation, n = 28). Height velocity HV and total height gain were assessed during the 4-year study.
In both groups, HV and HV standard deviation score HV-SDSCA increased during treatment and decreased during observation periods. Interruption of treatment in the TOTO group did not result in a better gain in height standard deviation score H-SDSCA when compared with the TTOO group. After 4 years of study, the gain in H-SDSCA was 1.4 + or - 01 in the TOTO group and 1.6 + or - 0.2 in the TTOO group leading to a mean height of -2.0 + or - 1.0 SDS and -2.0 + or - 0.8 SDS, respectively. The rate of bone maturation was similar in the two groups.
In short SGA children, TOTO and TTOO regimens produced significant improvements in growth during r-hGH treatment. However, treatment interruption after 1 year did not influence the overall gain in height SDS when compared with 2 years' continuous treatment.
Hormone Research 02/2006; 66(3):118-23. DOI:10.1159/000093832 · 2.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Increasing evidence point to the role of the adipose tissue on the insulin resistance associated with reduced fetal growth. Since adiponectin, exclusively produced by the adipose tissue, exerts an important insulin-sensitizing activity, it appears critical to investigate the effect of being born small for gestational age (SGA) on adiponectin production in adulthood and its relationship with insulin sensitivity.
Serum adiponectin concentrations were measured in 486 young adults born SGA, precisely selected on birth data, who were compared to 573 age-matched subjects born appropriate for gestational age (AGA). The relationship between serum adiponectin levels and insulin-resistance indices measured under OGTT were tested and compared between the two groups.
The SGA group demonstrated significantly reduced serum adiponectin levels than controls (12.6 +/- 6.9 vs 13.2 +/- 6.4 microg/ml, P = 0.02) and the difference remained significant when the key regulatory factors were taken into account (P = 0.008). In the AGA group, fasting I/G taken as an insulin-resistance index negatively correlated with serum adiponectin concentrations (P = 0.02), while the relationship followed a U-shape with increased fasting I/G ratio despite high concentrations of serum adiponectin in the SGA group (P = 0.12).
Subjects born SGA demonstrated significantly reduced serum adiponectin levels, which were not related to insulin-resistance indices in comparison to what observed in age-matched subjects born AGA. Although this defect in adiponectin production and in its insulin-sensitizing action remains to be elucidated at the molecular level, it strengthens the critical contribution of the adipose tissue in the metabolic complications associated with reduced fetal growth.
International Journal of Obesity 02/2006; 30(1):83-7. DOI:10.1038/sj.ijo.0803106 · 5.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The metabolic and cardiovascular complications associated with in-utero undernutrition have been identified during the past 10 years. Reduced fetal growth is independently associated with an increased risk of development of cardiovascular diseases, the insulin-resistance syndrome or one of its components (i.e., hypertension, dyslipidaemia, impaired glucose tolerance and type 2 diabetes). Insulin resistance appears to be a key component underlying these metabolic complications. Although the mechanism remains unclear, several pieces of evidence support an active role of adipose tissue in the emergence of insulin resistance (an abnormal growth pattern and repartition, hypersensitivity to catecholamines, regulation of leptin and adiponectin secretion and modulation of peroxisome proliferator-activated receptor gamma). Among individuals born SGA, those who are more at risk of gaining excess adiposity are those who are thin at birth following a period of fetal growth restriction. This period of undernutrition is followed by a neonatal period of catch-up growth and renutrition. This pattern induces important modifications in adipose tissue, with long-term consequences, among which is a high risk of early development of insulin resistance. Not all individuals born SGA will show such modifications in adipose tissue, meaning that not all of those born SGA are at risk of insulin resistance and diabetes. From a broader point of view, several hypotheses have been proposed over the past 10 years to explain this unexpected association between being born SGA and the later development of disease. Each of them points to a detrimental fetal environment, to a genetic susceptibility or to interactions between these two components playing a critical role in this context. Although not confirmed, the hypothesis suggesting that this association could be the consequence of genetic/environmental interactions remains the most attractive.
[Show abstract][Hide abstract] ABSTRACT: Implication of the IGF-IGF-binding protein (IGFBP) axis in the development of metabolic and cardiovascular diseases has been well documented. It has also been shown that an adverse intrauterine environment alters the IGF-IGFBP axis during childhood.
The objective of this study was to investigate whether these alterations persist into adulthood.
Fasting serum IGF-I, IGFBP-3, and insulin concentrations were measured, and their determinants were analyzed in a cohort of young adult subjects (22 yr of age) born either small (SGA; n = 461) or appropriate (AGA; n = 568) for gestational age.
In adulthood, subjects born SGA had significantly lower mean serum IGF-I (320 +/- 137 vs. 348 +/- 143 microg/liter; P = 0.0015), IGFBP-3 (4700 +/- 700 vs. 4800 +/- 800 microg/liter; P = 0.04), and IGF-I/IGFBP-3 ratio (0.067 +/- 0.026 vs. 0.072 +/- 0.025; P = 0.01) than those born AGA. The fasting IGF-I concentration and the IGF-I/IGFBP-3 ratio were significantly inversely associated with age, body mass index, smoking, and oral contraception and were positively related to birth weight and fasting insulin levels. The IGFBP-3 concentration was significantly negatively correlated to age and smoking and was positively related to insulin concentration and oral contraception. After adjustment for age, height, body mass index, gender, smoking, and oral contraception, the mean IGF-I concentration and the mean IGF-I/IGFBP-3 ratio remained significantly lower in the SGA compared with the AGA group (P = 0.003 and P = 0.01, respectively).
Serum IGF-I concentrations and the IGF-I/IGFBP-3 ratio are lower in adult subjects born SGA. Although the origin of this persisting alteration of the IGF-IGFBP axis in adulthood needs to be elucidated, its potential contribution to the long-term metabolic and cardiovascular complications associated with fetal growth restriction is important to consider in the future.
[Show abstract][Hide abstract] ABSTRACT: Subjects born small for gestational age (SGA) who are prone to develop insulin resistance in adulthood display an abnormal development pattern of the adipose tissue during fetal and postnatal life. Since the lipolytic activity of the adipose tissue is critical in the development of insulin resistance, the purpose of this study was to investigate whether SGA itself might affect lipolysis regulation.
We studied the effect of catecholamines, by local injection of isoproterenol, and the effect of insulin, using two-step infusion at 8 and 40 mU/m2/min, on the in situ lipolysis of the subcutaneous abdominal adipose tissue of 23 subjects born SGA and 23 born appropriate for gestational age (AGA), using the microdialysis technique.
Under isoproterenol infusion, the increase in dialysate glycerol concentration was significantly 1.5-fold higher in the SGA than in the AGA group (P=0.02) and induced a 20% increase in the plasma FFA concentration (P=0.04), whereas no significant increase was observed in the AGA group. The antilipolytic action of insulin on dialysate glycerol concentration was similar in both groups throughout the insulin infusion.
Subjects born SGA demonstrated a hyperlipolytic reactivity to catecholamines, which might be regarded as an additional deleterious component of the insulin resistance associated with SGA. In contrast, being born SGA does not directly affect the antilipolytic action of insulin, showing that it does not play a major role in causing the long-term metabolic complications associated with reduced fetal growth.
International Journal of Obesity 07/2005; 29(6):565-70. DOI:10.1038/sj.ijo.0802901 · 5.00 Impact Factor