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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.

Context: Regular monitoring of serum IGF-I levels during growth hormone (GH) therapy has been recommended, for assessing treatment compliance and safety., Objective: To investigate serum IGF-I SDS levels during GH treatment in children with GH deficiency, and to identify potential determinants of these levels., Design, Patients and Methods: This observational cohort study included all patients ( n  = 308) with childhood-onset non-acquired or acquired GH deficiency (GHD) included in the database of a single academic pediatric care center over a period of 10 years for whom at least one serum IGF-I SDS determination during GH treatment was available. These determinations had to have been carried out centrally, with the same immunoradiometric assay. Serum IGF-I SDS levels were determined as a function of sex, age and pubertal stage, according to our published normative data., Results: Over a median of 4.0 (2-5.8) years of GH treatment per patient, 995 serum IGF-I SDS determinations were recorded. In addition to BMI SDS, height SDS and GH dose ( P  < 0.01), etiological group ( P  < 0.01) had a significant effect on serum IGF-I SDS levels, with patients suffering from acquired GHD having higher serum IGF-I SDS levels than those with non-acquired GHD, whereas sex, age, pubertal stage, treatment duration, hormonal status (isolated GHD (IGHD) vs multiple pituitary hormone deficiency (MPHD)) and initial severity of GHD, had no effect., Conclusions: These original findings have important clinical implications for long-term management and highlight the need for careful and appropriate monitoring of serum IGF-I SDS and GH dose, particularly in patients with acquired GHD, to prevent the unnecessary impact of potential comorbid conditions., (© 2017 European Society of Endocrinology.)

Objective: To assess in a pediatric population, the clinical characteristics and management of triiodothyronine-predominant Graves' disease (T3-P-GD), a rare condition well known in adults, but not previously described in children., Design: We conducted a university hospital-based observational study., Methods: All patients with GD followed for more than 1 year between 2003 and 2013 (n=60) were included. T3-P-GD (group I) was defined as high free T3 (fT3) concentration (>8.0 pmol/l) associated with a normal free thyroxine (fT4) concentration and undetectable TSH more than 1 month after the initiation of antithyroid drug (ATD) treatment. Group II contained patients with classical GD without T3-P-GD., Results: Eight (13%) of the patients were found to have T3-P-GD, a median of 6.3 (3.0-10.5) months after initial diagnosis (n=4) or 2.8 (2.0-11.9) months after the first relapse after treatment discontinuation (n=4). At GD diagnosis, group I patients were more likely to be younger (6.8 (4.3-11.0) vs 10.7 (7.2-13.7) years) and had more severe disease than group II patients, with higher serum TSH receptor autoantibodies (TRAb) levels: 40 (31-69) vs 17 (8-25) IU/l, P<0.04, and with slightly higher serum fT4 (92 (64-99) vs 63 (44-83) pmol/l) and fT3 (31 (30-46) vs 25 (17-31) pmol/l) concentrations. During the 3 years following T3-P-GD diagnosis, a double dose of ATD was required and median serum fT4:fT3 ratio remained lower in group I than in group II., Conclusion: Severe hyperthyroidism, with particularly high TRAb concentrations at diagnosis, may facilitate the identification of patients requiring regular serum fT3 determinations and potentially needing higher doses of ATD dosage during follow-up., (© 2015 European Society of Endocrinology.)

Context: Recently, in a 4-month proof-of-concept trial, beneficial metabolic effects were reported in non-diabetic children with Berardinelli-Seip congenital lipodystrophy (BSCL); this information prompted us to hypothesize that long-term leptin-replacement therapy might improve or reverse the early complications of the disease in these patients., Patients and Methods: A 28-month trial was implemented in eight patients. Efficacy assessment was based on a decrease in serum triglyceride concentrations, and/or a decrease in liver volume and/or an increase in insulin sensitivity of at least 30% respectively. The response was defined as follows: total (3/3 positive criteria), partial (1 or 2/3), or negative (0/3). Anti-leptin antibodies were measured with a radiobinding assay, and a neutralizing effect was assessed in primary cultures of embryonic neurons incubated with an apoptotic agent (N-methyl-D-aspartate) and the patient serum, with or without leptin., Results: A negative or partial response to treatment was observed in five of eight patients even when leptin dosages were increased. A displaceable leptin binding was detectable in all patients after 2 months of treatment. At 28 months, binding was higher in the patients with a negative response than in the total responders, and it paralleled both the increase in leptin dosage and serum leptin concentrations. Co-incubation of embryonic neurons with serum from two patients with a negative response inhibited the neuroprotective effect of leptin., Conclusion: Under leptin therapy, patients with BSCL may develop a resistance to leptin, which could be partly of immunological origin, blunting the previously reported beneficial effects.

Context: Early prophylactic thyroidectomy in patients with multiple endocrine neoplasia (MEN) type 2 offers the best chance for a normal life expectancy., Objective: To analyze the results of thyroidectomy performed during the first year of life in six patients with MEN 2A (codon 634) or MEN 2B (codon 918) syndrome., Design and Setting: A university hospital-based prospective study from 2001 to 2008., Subjects and Methods: Six family members affected either by MEN 2A (n=3) or MEN 2B (n=3) syndrome were identified through neonatal genetic screening., Results: Total thyroidectomy was performed at a median age of 0.8 year in the six patients, with central lymph node dissection in five. Bilateral millimetric medullary thyroid carcinoma (MTC) was found in all patients, with a unilateral lymph node micrometastasis in two of the three MEN 2B patients. Before thyroidectomy, MEN 2B patients had much higher basal serum calcitonin levels than those with MEN 2A and controls. After thyroidectomy, with a median follow-up of 3.3 years, the six patients had no evidence of persistent MTC., Conclusion: Bilateral millimetric MTC may be present during the first year of life in these patients, with lymph node metastases also occurring in MEN 2B patients. These results support a total thyroidectomy at the age of about one year in MEN 2A (codon 634) children with an abnormal serum calcitonin level, and a total thyroidectomy with central neck dissection within the first weeks of life in MEN 2B patients.

Background: Fetal growth restriction (FGR) has been related to several health risks, which have been generally identified in small-for-gestational age (SGA) individuals., Objective: To evaluate the impact of FGR on body composition and hormonal status in infants born either small- or appropriate-for-gestational age (AGA)., Methods: Fetal growth was assessed by ultrasound every 4 weeks from mid-gestation to birth in 248 high-risk pregnancies for SGA. Fetal growth velocity was calculated as change in the estimated fetal weight percentiles and FGR defined as its reduction by more than 20 percentiles from 22 gestational weeks to birth. Impact of FGR on body composition, cord insulin, IGF-I, IGF binding protein-3 (IGFBP-3), and cortisol concentrations was assessed in SGA and AGA newborns., Results: Growth-retarded AGA infants showed significantly reduced birth weight, ponderal index, percentage of fat mass, and bone mineral density when compared with AGA newborns with stable intrauterine growth. Cord IGF-I and IGFBP-3 concentrations were significantly decreased in growth-retarded infants in both SGA and AGA groups. Cord insulin concentration was significantly lower and cord cortisol significantly higher in AGA infants with FGR versus AGA newborns with stable intrauterine growth. After adjustment for gestational age and gender, birth weight was directly related to fetal growth velocity and cord IGF-I concentration. The variation in infant's adiposity was best explained by fetal growth velocity and cord insulin concentration., Conclusions: FGR affects body composition and hormonal parameters in newborns with birth weight within the normal range, suggesting these individuals could be at similar metabolic risks as SGA. .

Context: There is evidence to suggest that IGF-I plays a role in regulating bone turnover., Objective: To evaluate the relationships between serum concentrations of IGF-I and IGF-binding protein-3 (IGFBP-3), and bone metabolism markers in healthy children., Design and Setting: Prospective cross-sectional study., Subjects and Methods: A cohort of 579 boys and 540 girls, all healthy Caucasian, were included in this study. Serum IGF-I and IGFBP-3 concentrations, bone alkaline phosphatase (BAP) and CrossLaps (markers of bone formation and bone resorption respectively) levels were evaluated as a function of age, gender, pubertal stage and body mass index., Results: Serum IGF-I SDS levels were positively correlated with BAP and CrossLaps SDS levels before and after puberty, and also with CrossLaps during puberty (weak correlation). Serum IGFBP-3 SDS levels were positively correlated with BAP and CrossLaps levels before, during (weak correlation) and after puberty (for BAP levels only)., Conclusions: This study demonstrated the independent association between serum IGF-I and IGFBP-3 concentrations with both serum bone formation and resorption markers in healthy children. Physiological differences before, during and after puberty in the association of serum IGF-I and IGFBP-3 levels with the serum bone metabolism markers were found. These differences may be related to differences in interactions between sex steroid hormones and the GH/IGF-I system, bone metabolism and growth during the pubertal transition. Improvements in our understanding of life course determinants of the IGF-I system and bone metabolism are required to shed further light on the role of the GH/IGF-I axis in bone remodelling.