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Juliane Léger, Isabelle Mercat, Corinne Alberti, Didier Chevenne, Priscilla Armoogum, Jean Tichet and Paul Czernichow

Abstract

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.

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Juliane Léger, Damir Mohamed, Sophie Dos Santos, Myriam Ben Azoun, Delphine Zénaty, Dominique Simon, Anne Paulsen, Laetitia Martinerie, Didier Chevenne, Corinne Alberti, Jean-Claude Carel and Sophie Guilmin-Crepon

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.

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Julie Harvengt, Priscilla Boizeau, Didier Chevenne, Delphine Zenaty, Anne Paulsen, Dominique Simon, Sophie Guilmin Crepon, Corinne Alberti, Jean-Claude Carel and Juliane Léger

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.

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Jacques Beltrand, Najiba Lahlou, Tifenn Le Charpentier, Guy Sebag, Sofia Leka, Michel Polak, Nadia Tubiana-Rufi, Didier Lacombe, Marc de Kerdanet, Frederic Huet, Jean-Jacques Robert, Didier Chevenne, Pierre Gressens and Claire Lévy-Marchal

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.