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Завантажено з https://academic.oup.cOm/jcem/article-abstract/92/3/804/25968918 ЧЕРВНЯ 2018.НАДРУКОВАНО В СШАTHE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 92(3):804 – 810PRINTED IN U.S.A.COPYRIGHT © 2007 BY THE ENDOCRINE SOCIETY DOI: 10.1210/JC.2006-2017Мета: Низька маса тіла залишається основною причиною захворюваності та смертності в ранньому віці та дитинстві. Це пов’язано з підвищеним ризиком виникнення проблем зі здоров’ям пізніше в житті, зокрема ішемічної хвороби серця та інсульту. Булa скликана нарада з метою виявлення основних проблем охорони здоров’я, що стоять перед дитиною, народженою з малою відносно гестаційного віку (МГВ) - small for gestational age (SGA), і як результат запропонувати стратегії ведення таких дітей.Учасники: були обрані 42 учасники на основі їх попередніх досліджень та обстежень в акушерстві, перинатальній та неонатальній медицині, педіатрії, педіатричній та дорослій ендокринології, епідеміології та фармакології.Докази: відбувся обмін письмовими матеріалами, вони були переглянуті, оцінені, а потім відкриті для всіх учасників. Це сформувало дискусійну базу засідання. Якщо опубліковані дані виявлялись недоступними або неадекватними, дискусія грунтувалася в такому разі на думках клінічних експертів.Процес консенсусу: кожна група питань була розглянута усіма учасниками, а потім обговорена на пленарних засіданнях за допомогою консенсусу та визначення невирішених питань. Консенсусну заяву було підготовлено на пленарному засіданні сесії, з подальшим редагуванням групами фахівців, після чого вона стала доступною для ознайомлення всім учасникам засідання.Висновки: Діагноз МГВ повинен грунтуватися на точній антропометрії при народженні, включаючи масу, довжину та об’єм голови. Ми рекомендуємо ранній нагляд у клініці росту для тих, хто не досягає необхідних параметрів. Оцінка раннього нейророзвитку та втручання у дітей ризикового віку. Ендокринні та метаболічні порушення у дитині МГВ визнаються, але рідко. Для 10%, хто не надолужує показників, лікування МГВ може збільшити лінійний ріст. Раннє втручання з GH для тих, хто має серйозну затримку в зростанні (висота за SD шкалою

Our objectives were to describe, in Beagle dogs, the ontogenesis of beta (insulin-producing) and alpha (glucagon-producing) cells from fetal to early postnatal life and adulthood. In addition, to have some insight into interspecies comparison, Beagle dog pancreases were compared to pancreases from a Labrador and Chow Chow. At midgestation, the epithelium was dense, beta cells scarce, and alpha cells numerous and concentrated in the center of the pancreatic bud. From 36 to 45 days post conception (pc), beta cell numbers increased and the epithelium expanded and branched out. At 55 days pc, large beta cell aggregates were seen. At weaning, the islets were similar to those in adults, with limited alpha cells intermingled with numerous beta cells. Quantification of the Alpha to Beta cells ratio has shown a gradual increase of beta cells proportion throughout development. Similar findings were obtained in the two other breeds. In conclusion, in the fetal Beagle dog beta cells emerge from the pancreatic bud at midgestation, but the endocrine structure is mature only in early postnatal life. The ontogenesis of the endocrine pancreas demonstrated in dogs resembles that reported in rats and mice. In contrast, human beta cells appear earlier, at the beginning of the second trimester of gestation. Our study provides a detailed morphological description of pancreatic development in dogs but supplies no information on alpha- or beta-cell function during fetal life. The morphological data reported here provide a foundation for building physiological studies.

To address questions regarding onset and progression of types 1 and 2 diabetes (T1D/T2D), surrogate imaging biomarkers for beta cell function and mass are needed. Here, we assess the potential of GPR44 as a surrogate marker for beta cells, in a direct comparison with clinically used biomarker VMAT2.GPR44 surface availability was assessed by flow cytometry of human beta cells. RNA transcription levels in different pancreas compartments were evaluated. The density of GPR44 receptor in endocrine and exocrine tissues was assessed by the radiolabeled GPR44 ligand [(3)H]AZD 3825. A direct comparison with the established beta cell marker VMAT2 was performed by radiolabeled [(3)H]DTBZ.GPR44 was available on the cell surface, and pancreatic RNA levels were restricted to the islets of Langerhans. [(3)H]AZD 3825 had nanomolar affinity for GPR44 in human islets and EndoC-βH1 beta cells, and the specific binding to human beta cells was close to 50 times higher than in exocrine preparations. The endocrine-to-exocrine binding ratio was approximately 10 times higher for [(3)H]AZD 3825 than for [(3)H]DTBZ.GPR44 is a highly beta cell-specific target, which potentially offers improved imaging contrast between the human beta cell and the exocrine pancreas.

Background/Objective: Normally sited glands account for increasing congenital hypothyroidism (CH). Mechanisms often remain unknown. To report the incidence of CH with in situ thyroid gland (ISTG) and describe the natural history of the disease without known etiology. Method: Clinical, biochemical and imaging data at diagnosis were retrospectively analyzed in 285 children positively screened for CH in Ile-de-France between 2005 and 2008. If treatment was discontinued, management of hormonal substitution and follow-up of biochemical thyroid function was performed. Results: 93 full-term CH neonates displayed ISTG (40.6%), including 50 with unexplained mechanism. Follow-up data were available in 32 of them. Therapy was withdrawn from 20 children at a median age of 23.5 months (6-66), among whom 18 remained still untreated over a median duration of 15.3 months (4.4-29.6). In 11 children, levothyroxine (L-T4) dosage was increased over time to maintain biochemical euthyroidism. No statistical differences in initial TSH or FT4 levels, iodine status or birth weight were found between children with transient and permanent hypothyroidism. Conclusion: Withdrawal of L-T4 substitution was feasible in 56.2% of full-term children with CH with ISTG but unexplained mechanism, emphasizing the need for systematic therapy withdrawal. However, further studies are warranted to standardize withdrawal protocol.

International audience; Diabetic patients exhibit a reduction in β cells, which secrete insulin to help regulate glucose homeostasis; however, little is known about the factors that regulate proliferation of these cells in human pancreas. Access to primary human β cells is limited and a challenge for both functional studies and drug discovery progress. We previously reported the generation of a human β cell line (EndoC-βH1) that was generated from human fetal pancreas by targeted oncogenesis followed by in vivo cell differentiation in mice. EndoC-βH1 cells display many functional properties of adult β cells, including expression of β cell markers and insulin secretion following glucose stimulation; however, unlike primary β cells, EndoC-βH1 cells continuously proliferate. Here, we devised a strategy to generate conditionally immortalized human β cell lines based on Cre-mediated excision of the immortalizing transgenes. The resulting cell line (EndoC-βH2) could be massively amplified in vitro. After expansion, transgenes were efficiently excised upon Cre expression, leading to an arrest of cell proliferation and pronounced enhancement of β cell–specific features such as insulin expression, content, and secretion. Our data indicate that excised EndoC-βH2 cells are highly representative of human β cells and should be a valuable tool for further analysis of human β cells.

Innovative treatments to cure type 1 diabetes are being actively researched. Among the different strategies, the replacement of β-cells has given promising results. Classically, islets from cadaveric donors are transplanted into diabetic patients, but recently phase I clinical trials that use stem cell-derived β-cells have been started. Such protocols require either an immunosuppressive treatment or the macroencapsulation of the β-cells. They involve cell aggregation and the exposure of the cells to hypoxia. Using an engineered human β-cell, we have addressed these two problems: a novel human β-cell line called EndoC-βH3 was cultured as single cells or aggregated clusters. EndoC-βH3 cells were also cultured at normal atmospheric oxygen tension (pO2 = 21%) or hypoxia (pO2 = 3%) in the presence or absence of modulators of the hypoxia-inducible factor 1α (HIF1α) pathway. Cell aggregation improved glucose-stimulated insulin secretion, demonstrating the benefit of cell–cell contacts. Low oxygen tension decreased β-cell viability and their sensitivity to glucose, but did not alter insulin production nor the insulin secretion capacity of the remaining cells. To investigate the role of HIF1α, we first used a HIF stabilizer at pO2 = 21%. This led to a mild decrease in cell viability, impaired glucose sensitivity, and altered insulin secretion. Finally, we used a HIF inhibitor on EndoC-βH3 pseudoislets exposed to hypoxia. Such treatment considerably decreased cell viability. In conclusion, aggregation of the EndoC-βH3 cells seems to be important to improve their function. A fraction of the EndoC-βH3 cells are resistant to hypoxia, depending on the level of activity of HIF1α. Thus, these cells represent a good human cell model for future investigations on islet cell transplantation analysis.

We are writing as scientists and editors of leading peerreviewed journals that have published important contributions in the study of endocrine disrupting chemicals (EDCs). By signing this editorial, we affirm that regulatory decisions on EDCs should be made based on the best available science and expertise that involves, among others, reproductive biology, endocrinology, medicine, genetics, behavior, developmental biology, and toxicology. (For a complete list of Signatories and their Disclosures, see Supplemental Table 1 published on The Endocrine Society’s Journals Online website at http://end. endojournals.org.) Thousands of published studies have revealed the health effects of EDCs on wildlife and laboratory animals and, moreover, have shown associations of EDCs with effects in humans. Many of these studies have been reviewed recently by The Endocrine Society, the United Nations Environment Programme (UNEP), and World Health Organization (WHO), and other independent scientists. The conclusions presented in each of these documents are extraordinarily consistent: like hormones, EDCs are active at very low doses and can induce a range of adverse health outcomes, many of which are not examined in traditional toxicology assays. In sum, these reports point to the conclusion that EDCs pose a global health threat. A recent editorial signed by a number of editors of toxicology journals argues for the status quo in the regulation of EDCs, despite the large volume of evidence indicating that current regulations are ineffective in protecting human populations from these chemicals. As the UNEP/WHO report notes, the incidence of chronic disease is now greater than that of communicable disease; many of these diseases have an endocrine basis. Both experimental animal and epidemiology studies provide plausible causal links between EDCs and many of these diseases; for some, the data are sufficiently robust. The dismissive approach to endocrine disruption science put forth by Dietrich et al. is unfounded, as it is neither based on the fundamental principles of how the endocrine system works and how chemicals can interfere with its normal function, nor does it consider the consequences of that interference. Their letter also ignores a growing and rigorous body of literature on both endogenous hormonal and exogenous EDC effects.

Normal growth is a sign of good health. Monitoring for growth disturbances is fundamental to children's health care. Early detection and diagnosis of the causes of short stature allows management of underlying medical conditions, optimizing attainment of good health and normal adult height. Conclusion This review summarizes currently available information on monitoring for short stature in children and conditions usually associated with short stature and summarizes the authors’ conclusions on the early recognition of growth disorders.

Aims/hypothesis Genetically engineered human beta cell lines provide a novel source of human beta cells to study metabolism, pharmacology and beta cell replacement therapy. Since the immune system is essentially involved in beta cell destruction in type 1 diabetes and after beta cell transplantation, we investigated the interaction of human beta cell lines with the immune system to resolve their potential for immune intervention protocol studies. Methods Human pancreatic beta cell lines (EndoC-βH1 and ECi50) generated by targeted oncogenesis in fetal pancreas were assessed for viability after innate and adaptive immune challenges. Beta cell lines were pre-conditioned with T helper type 1 (Th1) cytokines or high glucose to mimic inflammatory and hyperglycaemia-stressed conditions. Beta cells were then co-cultured with auto- and alloreactive cytotoxic T cells (CTL), natural killer (NK) cells, supernatant fraction from activated autoreactive Th1 cells, or alloantibodies in the presence of complement or effector cells. Results Low HLA expression protected human beta cell lines from adaptive immune destruction, but it was associated with direct killing by activated NK cells. Autoreactive Th1 cell inflammation, rather than glucose stress, induced increased beta cell apoptosis and upregulation of HLA, increasing beta cell vulnerability to killing by auto- and alloreactive CTL and alloreactive antibodies. Conclusions/interpretation We demonstrate that genetically engineered human beta cell lines can be used in vitro to assess diverse immune responses that may be involved in the pathogenesis of type 1 diabetes in humans and beta cell transplantation, enabling preclinical evaluation of novel immune intervention strategies protecting beta cells from immune destruction. Electronic supplementary material The online version of this article (doi:10.1007/s00125-015-3779-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Despite intense efforts over the past 30 years, human pancreatic β cell lines have not been available. Here, we describe a robust technology for producing a functional human β cell line using targeted oncogenesis in human fetal tissue. Human fetal pancreatic buds were transduced with a lentiviral vector that expressed SV40LT under the control of the insulin promoter. The transduced buds were then grafted into SCID mice so that they could develop into mature pancreatic tissue. Upon differentiation, the newly formed SV40LT-expressing β cells proliferated and formed insulinomas. The resulting β cells were then transduced with human telomerase reverse transcriptase (hTERT), grafted into other SCID mice, and finally expanded in vitro to generate cell lines. One of these cell lines, EndoC-βH1, expressed many β cell-specific markers without any substantial expression of markers of other pancreatic cell types. The cells secreted insulin when stimulated by glucose or other insulin secretagogues, and cell transplantation reversed chemically induced diabetes in mice. These cells represent a unique tool for large-scale drug discovery and provide a preclinical model for cell replacement therapy in diabetes. This technology could be generalized to generate other human cell lines when the cell type-specific promoter is available.

Objectives: To describe glucose metabolism changes during growth hormone (GH) treatment in juvenile idiopathic arthritis (JIA). Study Design: Observational study in 58 children on glucocorticoid therapy (GC) for JIA, of whom 28 received late GH therapy (7.3 ± 3.4 years into GC), 15 early GH therapy (1.2 ± 0.1 years into GC), and 15 no GH therapy. The GH dose was 0.46 mg/kg/week. Oral glucose tolerance testing with insulin and glycosylated hemoglobin assays were performed yearly. Nonparametric tests were used to compare groups after 3 years and regression analyses to estimate factors predicting glucose AUC and HOMA-IR at baseline and after 3 years. Results: GH combined with GC was associated with an increase in mean fasting insulinemia. Late GH therapy patients exhibited significant increases over time in mean fasting glycemia (p = 0.01), mean 2-hour postglucose load glycemia (p < 0.05), mean AUC for glucose (p < 0.05), and mean HOMA-IR (p < 0.05). Impaired glucose tolerance was found in 16/43 GH-treated patients (37%) and transient diabetes in 2 (5%) patients. Conclusions: GH treatment in JIA children decreased insulin sensitivity but had only modest effects on glucose tolerance. Close monitoring by oral glucose tolerance testing is crucial before and during GH treatment, particularly during puberty and relapses.

Although steroid-free remission can usually be achieved with cyclosporin A (CsA) in patients with steroid-dependent nephrotic syndrome (SDNS), some CsA-treated patients require long-term steroid therapy. Data on growth in these patients are scarce. Sixty-four boys with SDNS receiving long-term CsA and steroid therapy were retrospectively analyzed. During the 10-year follow-up period, height standard deviation score (HSDS) remained in the normal range in 47 patients but was below -2 SD in 17 patients. The occurrence of growth retardation was influenced by height at diagnosis and the number of relapses. Thirty patients were followed for at least 3 years before and after age 12. The decrease in HSDS per year of disease in patients older than 12 years was twice that observed in children younger than 12. However, adult height wasor = -2 SD in only two of the 14 patients reaching adult height, reflecting potential catch-up growth during late puberty. Careful monitoring of growth is recommended, given than up to 25% of patients experienced severe growth retardation during the course of their disease.

There is debate about how Graves' disease (GD) should be treated in children.The aim of this study was to identify predictors of relapse after antithyroid drug (ATD) treatment in children with GD.We conducted a prospective, multicenter cohort study of children (n = 154) with GD treated with carbimazole for an intended duration of 24 +/- 3 months. After the end of treatment, patients were followed up for at least 2 yr. The primary outcome was hyperthyroidism relapse. Cox's regression analysis was used and a prognostic score was constructed.The overall estimated relapse rate for hyperthyroidism was 59% (95% confidence interval 52-67%) at 1 yr and 68% (95% confidence interval 60-76%) at 2 yr after the end of treatment. Multivariate survival analysis showed that the risk of relapse was higher for patients of non-Caucasian origin [hazard ratio (HR) = 2.54, P0.001], with high serum thyroid-stimulating hormone receptor antibodies (HR = 1.21 by 10 U, P = 0.03) and free T(4) (HR = 1.18 by 10 pmol/liter, P = 0.001) levels at diagnosis. Conversely, relapse risk decreased with increasing age at onset (HR = 0.74 per 5 yr, P = 0.03) and duration of first course of ATD (HR = 0.57 per 12 months, P = 0.005). A prognostic score was constructed, allowing the identification of three different risk groups, with 2-yr relapse rates of 46, 77, and 98%.A longer initial duration of euthyroid state with ATD seems to be the only variable related to the risk of hyperthyroidism relapse in children that can be manipulated. Ethnic origin, age, and severity of the disease at diagnosis may guide long-term disease management decisions.

Context: The unexpected observation of a normal GH peak in 22% of young adults with childhood-onset GH deficiency (GHD) and ectopic neurohypophysis has raised questions about the criteria defining GHD in young adults and whether patients with subsequent increases in GH secretion nonetheless have a subtle form of GHD.Objective: Our objective was to determine the characteristics of patients with childhood-onset nonacquired GHD who recover normal peak GH secretion when adult height has been achieved.Design and Setting: We conducted a university hospital-based observational follow-up study.Participants: Sixty-two patients with ectopic neurohypophysis (n = 24), isolated hypoplastic anterior pituitary (n = 14), or normal hypothalamic pituitary area (n = 24) on magnetic resonance imaging (MRI) at the time of GHD diagnosis underwent reevaluation of the GH-IGF-I axis at a mean age of 16.8 ± 1.6 yr.Main Outcome Measures: Outcome measures included clinical and MRI findings and serum IGF-I and peak GH levels.Results: On retesting, peak GH exceeded 10 μg/liter in 31 patients (50%): six (20%) patients with ectopic neurohypophysis, 10 (32%) patients with initially isolated hypoplastic anterior pituitary, and 15 (48%) patients with normal MRI findings. Among these patients, serum IGF-I levels were significantly lower in patients with ectopic neurohypophysis than in those without structural abnormalities of the hypothalamic pituitary axis (n = 25), but patients without structural abnormalities also had significantly lower serum IGF-I levels than control subjects, after controlling for age, sex, and body mass index (mean serum IGF-I levels of 374 ± 83 vs. 446 ± 108 μg/liter; β-coefficient = −72; P = 0.003).Conclusions: The severity of the disease seems to have decreased over time in these patients, who may nonetheless present persistent pituitary failure. The natural history and clinical implications of these findings remain to be clarified. The possibility of a deterioration in the secretion of GH and other pituitary hormones later in life in a subset of these patients warrants the careful long-term follow-up of this population.

Familial cases of congenital hypothyroidism from thyroid dysgenesis (TD) (OMIM 218700) occur with a frequency 15-fold higher than by chance, FOXE1 is one of the candidate genes for this genetic predisposition and contains an alanine tract. Our purpose is to assess the influence of length of the alanine tract of FOXE1 on genetic susceptibility to TD. A case-control association study (based on 115 patients affected by TD and 129 controls genotyped by direct sequencing) and transmission disequilibrium testing (TDT) analyses were performed. The transcriptional activities of FOXE1 constructs containing 14 or 16 alanines were also studied. In the case-control association study, the 16/16 and 16/14 genotypes were inversely associated with TD (OR = 0.39, 95%CI = 0.22-0.68, P = 0.0005), strongly suggesting that the presence of 16 alanines in the tract protect against the occurrence of TD. This association was stronger in the subgroup of patients with ectopic thyroid (OR = 0.28, 95%CI = 0.13-0.58, P = 0.00015). The protection was confirmed by the TDT analysis performed in 39 trios (chi(2) = 4.3, P = 0.0374). Alternatively, the presence of the 14/14 genotype is associated with an increase risk of TD (OR = 2.59, 95%CI = 1.56-4.62, P = 0.0005). The expression studies showed that the transcriptional activities of FOXE1 with 16 alanines were significantly higher (1.55-fold) than FOXE1 containing 14 alanines (P0.003), while the nuclear localisation of the proteins was not affected. We conclude that FOXE1 through its alanine containing stretch modulates significantly the risk of TD occurrence, enhancing a mechanism linking an alanine containing transcription factor to disease.

Long-term glucocorticoid therapy adversely affects growth and body composition in children with juvenile idiopathic arthritis (JIA). In previous studies, recombinant human GH (rhGH) halted the progression of these complications without inducing catch-up growth.The objective of the study was to evaluate the impact on growth and body composition of rhGH started early after glucocorticoid initiation and to record adverse effects in children with JIA.This is a 3-yr randomized controlled study.This study was conducted in a teaching hospital.Thirty children, 12-15 months into glucocorticoid therapy for severe JIA, were enrolled.Patients received rhGH (0.46 mg/kg.wk) in daily sc injections (n = 15) or no rhGH therapy (n = 15) for 3 yr.Difference in height sd score (SDS) change between the two groups was assessed. Height velocity, body composition, and oral glucose tolerance were evaluated yearly.Mean height SDS increase was larger with rhGH (+0.37 +/- 1.5 SDS) than without (-0.96 +/- 1.2 SDS) (P = 0.04). Mean height velocity returned to normal within the first year of rhGH treatment and remained normal thereafter. Mean lean mass increase was greater with rhGH treatment (+7.3 +/- 2.9 kg vs. +4.4 +/- 2.8 kg; P = 0.03). Fat mass and bone mineralization were not significantly different in the two groups. Fasting serum insulin increased significantly in rhGH-treated patients (5.2 +/- 16 mIU/liter) compared with untreated controls (-2.3 +/- 5 mIU/liter) (P = 0.04); fasting glycemia was unchanged.rhGH started early in the course of JIA preserved normal growth velocity and height. Although rhGH was well tolerated, carbohydrate metabolism should be monitored closely.

Context: GH deficiency (GHD) associated with central precocious puberty (CPP) has been widely reported in cases of arachnoid cyst, septo-optic dysplasia, brain tumors, or after cerebral radiation therapy. However, idiopathic GHD associated with CPP has been reported in only one isolated case. Objective: To evaluate the occurrence and clinical features of the association of nonacquired GHD and CPP. Design and setting: This was a retrospective multicenter study. Patients and methods: The study population was identified through a French nationwide multicenter network (about 3000 patients). We reviewed the medical records of all subjects diagnosed with nonacquired GHD and CPP, with or without developmental abnormalities of the hypothalamic–pituitary axis on cerebral magnetic resonance imaging (MRI), and without any known associated anomaly. Results: We identified four patients with either isolated GHD (n = 1) or multiple anterior pituitary hormone deficiencies (n = 3). Clinical signs of CPP occurred at 6.4 ± 2.3 years in boys and 7.5 ± 0.5 years in girls, and GnRH analog therapy was started at 4.2 ± 1.6 years after the initiation of recombinant human GH treatment. Cerebral MRI demonstrated ectopic neurohypophysis associated with anterior pituitary hypoplasia in three out of the four patients. The morphology and position of the anterior pituitary and neurohypophysis were normal in one patient who displayed a persistence of the craniopharyngeal canal. Conclusions: CPP is very rare in patients with nonacquired GHD and is mostly associated with developmental defects in the hypothalamic–pituitary area. Whether molecular mechanisms governing development and activation of the hypothalamic–pituitary axis share dependent factors remains to be explored.

Depending on the definitions used, up to 10% of all live-born neonates are small for gestational age (SGA). Although the vast majority of these children show catch-up growth by 2 yr of age, one in 10 does not. It is increasingly recognized that those who are born SGA are at risk of developing metabolic disease later in life. Reduced fetal growth has been shown to be associated with an increased risk of insulin resistance, obesity, cardiovascular disease, and type 2 diabetes mellitus. The majority of pathology is seen in adults who show spontaneous catch-up growth as children. There is evidence to suggest that some of the metabolic consequences of intrauterine growth retardation in children born SGA can be mitigated by ensuring early appropriate catch-up growth, while avoiding excessive weight gain. Implicitly, this argument questions current infant formula feeding practices. The risk is less clear for individuals who do not show catch-up growth and who are treated with GH for short stature. Recent data, however, suggest that long-term treatment with GH does not increase the risk of type 2 diabetes mellitus and the metabolic syndrome in young adults born SGA.

Growth acceleration and bone maturation were studied for 3 y in 69 children with severe short stature and a history of intrauterine growth retardation (IUGR), to determine the effect of treatment with recombinant human growth hormone (r-hGH). The patients were enrolled in an open, multicentre trial and were randomly allocated to either the treated group (Group 1) or the control group (Group 2). The children in Group 1 were treated daily with 0.2 IU/kg/body weight (0.067 mg/kg) s.c., during 3 y and the children in Group 2 started the study with a 1-y observation period followed by a 3-y treatment period. At birth, their mean weight standard deviation score (SDS) was -2.5 and their mean length SDS -3.5. At baseline, the patients were prepubertal, non-GH deficient, with no known dysmorphic features. Mean age was 4.5 y, bone age was 3.3 y, height SDS was -3.4, height velocity (HV) SDS was -1.6, and body mass index SDS was -1.4. After 1 y of treatment, linear HV in Group 1 increased in comparison with the pre-treatment period (from 5.7 +/- 2.0 to 10.1 +/- 1.7 cm/y; p < 0.001) and with the first year of observation in Group 2 (p < 0.001). Increased HV was sustained during the second and third year of treatment and was significantly higher than at baseline. A similar growth pattern was seen during the 3 y of GH treatment in Group 2. Mean height SDS for chronological age increased by 2.0 +/- 0.7 in the two groups after 3 y of treatment. HV after 1 y of treatment was negatively correlated with growth velocity at baseline. Bone age remained retarded but increased with a mean of almost 4 y after 3 y of treatment in both groups. Even at a dose that is three times the replacement dose treatment with r-hGH was well tolerated. From these results, we conclude that r-hGH treatment over 3 y can induce sustained catch-up growth in young children with severe short stature and a history of IUGR. Long-term studies are needed to assess ultimate effects on final height.

In order to define more precisely the risk of hypoglycaemia in GH-deficient children and to clarify the role of growth hormone (GH) in glucose homeostasis, a 24-h fast was monitored in 10 GH-deficient children aged 1.1-6.5 y. Asymptomatic hypoglycaemia (blood glucose < or = 2.6 mmol/l) occurred in 9/10 children, 2 of whom prematurely interrupted the test. Blood glucose profile was not reproducible between children and had no correlation with age (p = 0.48). Gluconeogenesis was considered as non-altered as read from the normal plasma lactate and pyruvate concentrations throughout the test. Plasma ketone body concentrations increased during the test, but were lower than expected with respect to the decrease of blood glucose. This suggests insufficient ketogenesis which could exacerbate hypoglycaemia in GH-deficient children if brain glucose utilization were not alleviated by ketone body oxidization, as is normally the case. The positive glucose response after glucagon stimulation in 6/10 patients indicated normal hepatic glycogen content. However, these responses were unexpected following the prolonged fast and its concomitant hypoglycaemia, and would therefore tend to suggest a defect in glycogenolysis. These results confirm the tendency to hypoglycaemia, even after infancy, in GH-deficient children. These hypoglycaemias may occur by different types of malfunctioning, such as insufficient ketogenesis or a defect in glycogenolysis. These hypotheses require confirmation by a more systematic study of the metabolic and hormonal changes that occur during fasting in both GH-deficient and normal children.

Background The ATP-sensitive potassium (KATP) channel, composed of the beta-cell proteins sulfonylurea receptor (SUR1) and inward-rectifying potassium channel subunit Kir6.2, is a key regulator of insulin release. It is inhibited by the binding of adenine nucleotides to subunit Kir6.2, which closes the channel, and activated by nucleotide binding or hydrolysis on SUR1, which opens the channel. The balance of these opposing actions determines the low open-channel probability, PO, which controls the excitability of pancreatic beta cells. We hypothesized that activating mutations in ABCC8, which encodes SUR1, cause neonatal diabetes. Methods We screened the 39 exons of ABCC8 in 34 patients with permanent or transient neonatal diabetes of unknown origin. We assayed the electrophysiologic activity of mutant and wild-type KATP channels. Results We identified seven missense mutations in nine patients. Four mutations were familial and showed vertical transmission with neonatal and adult-onset diabetes; the remain...

Iodide transport defect (ITD) is an autosomal recessive disorder resulting in varying degrees of congenital hypothyroidism (CH) with goiter and low or absent radioiodide uptake (RIUT), as determined by thyroid scintigraphy, and low iodide saliva to plasma ratio. Defects of the sodium/iodide symporter gene (NIS) have been shown to cause ITD.We describe molecular studies of NIS in a patient with ITD and genotype-phenotype correlation analysis in 31 patients with NIS defects reported worldwide.NIS sequencing and functional studies of the new NIS mutation in vitro were performed.In a newborn with symptomatic CH and a large goiter, thyroid scintigraphy showed no RIUT (0%). NIS sequencing identified the new homozygous mutation, R124H, in exon 2. This mutation was associated with abolition of iodide uptake in vitro when transfected in COS-7 cells. Immunocytochemical studies documented correct targeting of the mutated protein to the plasma membrane of transfected cells. Genotype-phenotype correlation analysis showed that the onset of hypothyroidism occurred during the neonatal period with four NIS mutations (neonatal onset of hypothyroidism genotype), during infancy with three NIS mutations (infancy onset of hypothyroidism genotype), and during childhood with three NIS mutations (childhood onset of hypothyroidism genotype). RIUT is a direct measure of residual NIS activity in vivo. Mean RIUT was lower in patients with the neonatal onset of hypothyroidism genotype (0.88 +/- 0.2%) than in the infancy onset of hypothyroidism (1.9 +/- 0.4%; P0.05) and childhood onset of hypothyroidism (2.6 +/- 0.7%; P0.05) genotypes.We identified a new NIS mutation, R124H, in a newborn with the complete clinical ITD phenotype. Genotype-phenotype correlations suggest that age at hypothyroidism onset may be genotype specific and may depend on genotype-specific residual NIS activity.

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.

Background: 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 µg/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. Methods: 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. Results: 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 ± 01 in the TOTO group and 1.6 ± 0.2 in the TTOO group leading to a mean height of –2.0 ± 1.0 SDS and –2.0 ± 0.8 SDS, respectively. The rate of bone maturation was similar in the two groups. Conclusions: 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.

Background: Fetuses from mothers with Graves’ disease may experience hypothyroidism or hyperthyroidism due to transplacental transfer of antithyroid drugs (ATD) or anti-TSH receptor antibodies, respectively. Little is known about the fetal consequences. Early diagnosis is essential to successful management. We investigated a new approach to the fetal diagnosis of thyroid dysfunction and validated the usefulness of fetal thyroid ultrasonograms. Methods: Seventy-two mothers with past or present Graves’ disease and their fetuses were monitored monthly from 22 wk gestation. Fetal thyroid size and Doppler signals, and fetal bone maturation were determined on ultrasonograms, and thyroid function was evaluated at birth. Thyroid function and ATD dosage were monitored in the mothers. Results: The 31 fetuses whose mothers were anti-TSH receptor antibody negative and took no ATDs during late pregnancy had normal test results. Of the 41 other fetuses, 30 had normal test results at 32 wk, 29 were euthyroid at birth, and one had moderate hypothyroidism on cord blood tests. In the remaining 11 fetuses, goiter was visualized by ultrasonography at 32 wk, and fetal thyroid dysfunction was diagnosed and treated; there was one death, in a late referral, and 10 good outcomes with normal or slightly altered thyroid function at birth. The sensitivity and specificity of fetal thyroid ultrasound at 32 wk for the diagnosis of clinically relevant fetal thyroid dysfunction were 92 and 100%, respectively. Conclusion: In pregnant women with past or current Graves’ disease, ultrasonography of the fetal thyroid gland by an experienced ultrasonographer is an excellent diagnostic tool. This tool in conjunction with close teamwork among internists, endocrinologists, obstetricians, echographists, and pediatricians can ensure normal fetal thyroid function.

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.

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.

Although necessary for a normal final height in individuals who were born small for gestational age (SGA), catch-up growth is associated with drastic changes in body composition that have been suspected to favor the later development of the long-term metabolic complications by promoting central adiposity; however, the specific contribution of catch-up itself on these later complications remains unclear. Therefore, the aim of the study was to characterize the dynamic changes in adiposity during childhood in individuals who were born SGA and to investigate their consequences on adulthood. The magnitude and the time course of postnatal changes in body mass index (BMI) relative to birth and their consequences on adult adiposity were investigated in 127 adults who were born SGA and had available serial anthropometric data in childhood (0-6 y) and adulthood. Catch-up in BMI, observed in 91% of individuals who were born SGA, was mostly completed within the first or second year of age. Overall, adult BMI was correlated with the magnitude of gain in BMI during childhood. However, this effect was significant only when this gain persisted after the first year of life. Similarly, the influence of the magnitude in gain in BMI on the risk for adult BMI25 kg/m(2) was significantly influenced by the age at which the gain in BMI occurred. In summary, although the extent of catch-up in BMI affects adiposity in adulthood, this effect is mostly deleterious when occurring after 1 y of age, suggesting that a rapid catch-up process should be more suitable than a delayed one. Whether this observation holds through regarding the metabolic syndrome remains to be elucidated.

The aims of this study were to establish the role of insulin resistance in the metabolic syndrome associated with restricted fetal growth and to characterise the fetal and postnatal determinants responsible for the long-term metabolic outcome.The study population consisted of adults selected on birth data from a maternity registry and born either small for gestational age (SGA) (n=734, birthweighttenth percentile) or appropriate for gestational age (AGA) (n=886, 25thbirthweight75th percentile) and in whom clinical and metabolic parameters of the metabolic syndrome were measured at 22 years of age.Mean values of all components of the metabolic syndrome significantly differed between the two groups, with the metabolic syndrome observed in 2.3% of the SGA group and in 4 per thousand of the AGA group (p=0.0004). In SGA subjects, the upper tertile of fasting insulinaemia was associated with the highest values of systolic (p=0.001) and diastolic (p=0.02) blood pressure, triglyceridaemia (p=0.005) and glycaemia at fasting (p=0.0001) and during OGTT (p=0.0001). In SGA subjects, insulin resistance was not related to birthweight itself (p=0.26), but correlated negatively with BMI at birth (p=0.03) and positively with the subsequent postnatal catch-up in BMI (p=0.009).Insulin resistance is the keystone of metabolic syndrome associated with SGA, and its origin should be sought in the fetal development process of adiposity that is responsible for postnatal growth and the later development of insulin resistance.

OBJECTIVE To determine the proportion of the various types of thyroid disorders among newborns detected by the neonatal TSH screening programme, with a normally located thyroid gland. Patients and methods Of the 882 575 infants screened in our centre between 1981 and 2002, 85 infants with a normally located gland had persistent elevation of serum TSH values (an incidence of 1/10 383). Six of these 85 patients were lost to follow-up and were therefore excluded from the study. During follow-up, patients were classified as having permanent or transient hypothyroidism. RESULTS Among the 79 patients included in the study, transient (n = 30, 38% of cases) and permanent (n = 49, 62% of cases) congenital hypothyroidism (CH) was demonstrated during the follow-up at the age of 0.7 +/- 0.6 years and 2.6 +/- 1.8 years (P < 0.0001), respectively. The proportion of premature births was significantly higher in the group with transient CH (57%) than in the group with permanent CH (2%) (P < 0.0001). A history of iatrogenic iodine overload was identified during the neonatal period in 69% of transient cases. Among permanent CH cases (n = 49), patients were classified as having a goitre (n = 27, 55% of cases), a normal sized and shaped thyroid gland (n = 14, 29% of cases) or a hypoplastic gland (n = 8, 16% of cases). The latter patients demonstrated global thyroid hypoplasia (n = 3), a right hemithyroid (n = 2), hypoplasia of the left lobe (n = 2), or asymmetry in the location of the two lobes (n = 1). Patients with a normal sized and shaped thyroid gland showed a significantly less severe form of hypothyroidism than those with a goitre or a hypoplastic thyroid gland (P < 0.0002). Among permanent CH cases, those with a goitre (n = 27) had an iodine organification defect (n = 10), Pendred syndrome (n = 1), a defect of thyroglobulin synthesis (n = 8), or a defect of sodium iodine symporter (n = 1), and in seven patients no aetiology could be determined. Among permanent cases with a normal sized and shaped thyroid gland (n = 14), a specific aetiology was found in only one patient (pseudohypoparathyroidism) and two patients had Down's syndrome. Among those with a globally hypoplastic gland, a TSH receptor gene mutation was found in two patients. CONCLUSIONS A precise description of the phenotype can enhance our understanding of various forms of neonatal hypothyroidism as well as their prevalence and management. It also helps to identify cases of congenital hypothyroidism of unknown aetiology, which will need to be investigated in collaboration with molecular biologists.

Cerebral magnetic resonance imaging findings are of great value for the diagnosis of nonacquired GH deficiency (GHD), and ectopic posterior pituitary hyperintense signal (EPPHS) is a sensitive and specific indicator of hypopituitarism. It has been suggested that patients with childhood-onset GHD and EPPHS do not require additional investigation of GH secretion and should not be retested when adult height is achieved. This recommendation has never been validated through a systematic study. This study aimed to characterize the anterior pituitary function status of patients with EPPHS treated for GHD during childhood after completion of GH therapy when adult height had been achieved. Patients (n = 18; 15 males and three females) with childhood-onset GHD associated with ectopic neurohypophysis were treated with hGH (0.20 ± 0.05 mg/kg·wk) for 9.9 ± 4.0 yr (from 6.8 ± 4.7 to 17.7 ± 1.3 yr of age) with a mean height gain of 2.6 ± 1.4 sd score. GH secretion was reevaluated by arginine insulin (n = 15) or propanolol glucagon (n = 3) test after 0.5 ± 0.6 yr of GH withdrawal. At reevaluation, peak GH was more than 10 μg/liter in four patients (22%; range, 11.7–19.5 μg/liter; group I), between 5 and 10 μg/liter in three patients (17%; range, 7.3–9 μg/liter; group II), and less than 5 μg/liter in 11 patients (61%; range, 0–4.7 μg/liter; group III). A positive correlation was found between serum IGF-I and peak GH levels after attainment of adult height (P = 0.007). Only one of the seven patients who showed increased GH secretion ability in adulthood (groups I and II) demonstrated other hormonal deficiencies (gonadotropin and adrenal insufficiencies). Among the 11 patients with persistent severe GHD (group III), 10 (91%) of the 11 subjects were shown to have multiple pituitary hormone deficits after attainment of adult height. The structure of the hypothalamo-pituitary axis differs among groups [i.e. patients who showed increased GH secretion ability in adulthood (groups I and II) vs. those who remained severely GHD (group III)]. The location of the EPPHS was significantly different among groups (P < 0.003). The EPPHS was found at the median eminence in all but one of group III patients and along the pituitary stalk (proximal stalk) in all but one of group I and II patients. The pituitary stalk was visible and described as normal (n = 1) or thin (n = 6) in all group I and II patients, whereas the pituitary stalk was not visible even after enhancement in seven of the 11 group III patients (P < 0.02). The prevalence of anterior pituitary hypoplasia and the mean height gain sd score were similar in each group. In conclusion, only 61% of patients with childhood-onset GHD and EPPHS remained severely GHD, and thus suitable for GH therapy, in adulthood. Although the pathogenesis of anterior pituitary dysfunction remains unclear in patients with ectopic neurohypophysis, isolated GHD, location of EPPHS along the stalk, and visibility of the pituitary stalk on magnetic resonance imaging findings clearly represent important markers to predict a less severe form of the disease.

Androgen insensitivity syndrome: somatic mosaicism of the androgen receptor in seven families and consequences for sex assignment and genetic counseling. Abstract Androgen insensitivity syndrome (AIS) is caused by numerous mutations of the androgen receptor (AR) gene. The phenotype may range from partial AIS (PAIS) with ambiguous genitalia to complete AIS (CAIS) with female genitalia. In 70% of the cases, AR mutations are transmitted in an X-linked recessive manner through the carrier mothers, but in 30%, the mutations arise de novo. When de novo mutations occur after the zygotic stage, they result in somatic mosaicisms, which are an important consideration for both virilization in later life-because both mutant and wild-type receptors are expressed-and genetic counseling. We report here six patients with AIS due to somatic mutations of the AR and one mother with somatic mosaicism who transmitted the mutation twice. Of the four patients with PAIS, three presented spontaneous or induced virilization at birth or puberty. These cases underline the crucial role of the remnant wild-type AR for virilization because the same mutations, when they are inherited, lead to CAIS. We also report two novel mutations of the AR, with somatic mosaicism, detected in patients with CAIS. Thus, the remnant wild-type receptor does not always lead to virilization. In one of these patients, a high ratio of wild-type to mutant AR expression was found in the gonads and genital skin fibroblasts. Although no prenatal virilization occurred, the possibility of virilization at puberty could not be excluded, and early gonadectomy was performed. A seventh patient had a CAIS with a novel germline AR mutation. The mutation was inherited from the mother, in whom mosaicism was detected in blood and who transmitted the mutation to a second, XX, offspring. The detection of somatic AR mutations is particularly important for the clinical management and genetic counseling of patients with AIS. Before definite sex assignment, a testosterone treatment trial should be performed in all patients with PAIS, but it becomes crucial when an AR mosaicism has been detected. In patients with CAIS or severe PAIS raised as female, there is no consensus about when (early childhood or puberty) gonadectomy should be performed. When somatic AR mutations are detected, however, gonadectomy should be performed earlier because of the risk of virilization during puberty. When a germline de novo mutation is identified in the index case, the risk of transmission to a second child due to a possible germ cell mosaicism in the mother cannot be excluded. However, given the high number of AR de novo mutations and the rarity of such reports, this risk appears to be very low.

Thyroid dysgenesis (TD) is responsible for most cases of congenital hypothyroidism, a condition that affects about one in 4000 newborns. Mutations in PAX8, TITF1, or FOXE1 may account for congenital hypothyroidism in patients with either isolated TD or TD with associated malformations involving kidney, lung, forebrain, and palate. Pax8, titf1, and foxe1 are expressed in the mouse thyroid bud as soon as it differentiates on the pharyngeal floor. Because the spatio-temporal expression of these genes is unknown in humans, we decided to study them at different stages of human embryonic and fetal development. PAX8 and TITF1 were first expressed in the median thyroid primordium. Interestingly, PAX8 was also expressed in the thyroglossal duct and the ultimobranchial bodies. Human FOXE1 expression was detected later than in the mouse. PAX8 was also expressed in the developing central nervous system and kidney, including the ureteric bud and the main collecting ducts. TITF1 was expressed in the ventral forebrain and lung. FOXE1 expression was detected in the oropharyngeal epithelium and thymus. In conclusion, the expression patterns described here show some differences from those reported in the mouse. They explain the malformations associated with TD in patients carrying PAX8, TITF1, and FOXE1 gene mutations.

RESUME L’heterogeneite de la presentation du diabete sucre de l’enfant est en train de modifier notre approche de la maladie. Nous avons utilise la classification de l’American Diabetes Association (ADA) pour definir les differents types de diabete sucre presents dans une large cohorte d’enfants diabetiques avec le but de documenter l’emergence recente du diabete de Type 2 dans cette cohorte pediatrique. Les dossiers d’enfants ayant un diabete, âges entre 1 et 16 ans et admis dans notre centre entre 1993 et 1998 ont ete etudies pour les donnees permettant de classer le diabete sucre selon les criteres de l’ADA ; ils ont ete compares aux dossiers d’enfants admis pour diabete en 2001. Pendant la premiere periode, 370 enfants ont consulte pour diabete et chez 8 d’entre eux, le diagnostic de diabete de Type 2 a ete retenu. Sur une periode de un an en 2001, 90 enfants ont ete admis pour diabete et 5 d’entre eux ont eu un diagnostic de diabete de Type 2. L’incidence du diabete de Type 2 en France reste donc encore faible. Meme si nos chiffres semblent indiquer une discrete augmentation, ils sont encore loin des chiffres rapportes par les pediatres aux Etats-Unis. Cependant les cas observes en France sont marques par une obesite majeure. L’augmentation en France de l’obesite chez l’enfant fait craindre que l’incidence du diabete de Type 2 augmente dans notre pays avec la meme gravite qu’en Amerique du Nord.

Macrophages play an important role in organ development, tissue homeostasis, and remodeling. Thus, we monitored the presence of F4/80-positive macrophages in the pancreas of wild-type mice, and some developmental features of this complex tissue were compared throughout life in wild-type and macrophage-deficient Csf1op/Csf1op (op/op) mice. The combined use of immunohistochemistry, morphometry, and cell quantification allows us to evaluate insulin and glucagon cell mass, total and insulin cell proliferation, and apoptosis in fetuses (E18.5), weanings (postnatal day 21), nonpregnant adults, and adults in late pregnancy (18.5 days). F4/80-positive macrophages were found in pancreases recovered from Csf1op/Csf1+ (op/+) mice but were extremely scarce or absent in pancreas recovered from op/op ones at all studied time-points. The macrophage-deficient op/op phenotype was clearly associated with a major insulin mass deficit in fetuses and adults, abnormal postnatal islet morphogenesis, and impaired pancreatic cell proliferation at weaning and late pregnancy. We also obtained indirect evidence of increased neogenesis in this model at time-points when pancreatic remodeling does occur. The demonstration of the colony-stimulating factor 1-dependent macrophage involvement in life-time pancreas development/remodeling allows us to pinpoint the tissue-modeling and remodeling functions of this leukocyte lineage.

The abundance of published data on the neonatal effects of maternal Graves' disease (GD) contrasts with the paucity of information on fetal effects. In our yet unpublished study, we prospectively studied 72 pregnant women with a history of Graves' disease. Fetal ultrasonography was done at 22 and 32 weeks of gestational age. Fetal goiter was found at 32 weeks in 11 of the fetuses of the 41 mothers with positive TSH-receptor antibodies and/or antithyroid treatment and in none of the fetuses of the 31 other mothers. In the 11 fetuses with goiter, ultrasound findings (thyroid Doppler and bone maturation), fetal heart rate, and maternal antibody and antithyroid drug status effectively discriminated between hypothyroidism ( n =7) and hyperthyroidism ( n =4). One fetus with hyperthyroidism died in utero at 35 weeks from heart failure. Treatment was successful in the ten other fetuses. One fetus without goiter had moderate hypothyroidism at birth. This study showed that it is of the utmost importance to have the fetal thyroid scrutinized by an expert ultrasonographist and to have team work with obstetricians and paediatric endocrinologists in pregnant mothers with GD. This allowed us to accurately determine fetal thyroid status and to adapt the treatment in mothers successfully. Fetal hyperthyroidism does exist and needs an appropriate aggressive treatment.