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Juliane Léger and Jean-Claude Carel

Graves’ disease is an autoimmune disorder. It is the leading cause of hyperthyroidism, but is rare in children. Patients are initially managed with antithyroid drugs (ATDs), such as methimazole/carbimazole. A major disadvantage of treatment with ATD is the high risk of relapse, exceeding 70% of children treated for duration of 2 years, and the potential major side effects of the drug reported in exceptional cases. The major advantage of ATD treatment is that normal homeostasis of the hypothalamus–pituitary–thyroid axis may be restored, with periods of drug treatment followed by freedom from medical intervention achieved in approximately 40–50% of cases after prolonged treatment with ATD, for several years, in recent studies. Alternative ablative treatments such as radioactive iodine and, less frequently and mostly in cases of very high volume goiters or in children under the age of 5 years, thyroidectomy, performed by pediatric surgeons with extensive experience should be proposed in cases of non-compliance, intolerance to medical treatment or relapse after prolonged medical treatment. Ablative treatments are effective against hyperthyroidism, but they require the subsequent administration of levothyroxine throughout the patient’s life. This review considers data relating to the prognosis for Graves’ disease remission in children and explores the limitations of study designs and results; and the emerging proposal for management through the prolonged use of ATD drugs.

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Abdallah Al-Salameh, F Despert, Marie-Laure Kottler, Agnès Linglart, Jean-Claude Carel and Pierre Lecomte

Pseudohypoparathyroidism (PHP) covers a heterogeneous group of disorders, which have in common resistance to parathyroid hormone (PTH). However, they differ in many aspects such as site of the defect in signal transduction, clinical picture (with or without Albright's hereditary osteodystrophy (AHO)), extension of hormone resistance, and the tissue activity of protein Gs. PHP type Ic, a rare subtype, is characterized by resistance to several hormones, the presence of AHO, and normal activity of protein Gs. We present the case of a patient with PHP type Ic. Although resistance to TSH was suggested at the age of 12 months, diagnosis was made when she presented with hypocalcemia and resistance to PTH. Resistance to GH was also detected, and partial resistance to gonadotropins became clear after puberty. We demonstrated a defective lipolytic response to epinephrine, suggesting a role of this resistance in the pathogenesis of her morbid obesity. In view of the difficulties in the management of overweight in this disorder, treatment with a cannabinoid receptor type 1 (CB1) antagonist was started, and it proved to be highly effective, lowering the patient's body mass index from 40.5 to 33.5, which was quite impressive. We propose that an underactive melanocortin-4 receptor, which is found in certain patients with PHP, leads to upregulation of the CB1 receptor and consequently to a good response to treatment with CB1 antagonists. Another interesting finding was the GNAS mutation that was identified in this patient. A nonsense mutation resulted in a truncated Gsa that was able to stimulate adenylyl cyclase efficiently, but could not bind to receptors in a normal way.

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Hervé Lefevre, Claire Bouvattier, Najiba Lahlou, Catherine Adamsbaum, Pierre Bougnères and Jean-Claude Carel

Background: Peutz-Jeghers syndrome (PJS) is a rare autosomal-dominant disorder characterized by multiple gastrointestinal hamartomatous polyps, mucocutaneous pigmentation and increased predisposition to various neoplasms. Endocrine manifestations in PJS include gynecomastia due to calcified Sertoli cell testicular tumors usually referred to as large-cell calcifying Sertoli cell tumors (LSCT).

Objective: To evaluate the value of endocrine markers and aromatase inhibitor treatment in children with PJS and LSCT.

Design and setting: Familial cases, followed in a tertiary care center.

Patients: Two male siblings aged 7 and 9 years with PJS and LSCT.

Intervention: Third generation aromatase inhibitor (anastrozole) in one of the patients.

Main outcome measures: Longitudinal measurements of sex-steroids, gonadotropins, Sertoli cell markers and auxological evaluation.

Results: The two male siblings with PJS had similar bilateral multifocal testicular calcifications and biochemical evidence of Sertoli cell dysfunction manifested by elevated plasma inhibin-α levels. Only one sibling had gynecomastia. Estradiol levels were normal in both. During treatment with anastrozole, estradiol levels, growth and skeletal maturation, as well as Sertoli cell markers (inhibin B, inhibin-α and anti-Mullerian hormone) decreased.

Conclusions: Inhibin-α may be considered as a marker for LSCT in children with PJS, pointing to a specific defect in inhibin regulation in this condition. Moreover, the decrease in Sertoli cell markers during aromatase inhibitor treatment suggests that increased estrogen production is a primary event regulating downstream production of Sertoli cell peptides. Anastrozole is efficient in controlling the clinical features of the disease and should be proposed as an alternative to bilateral orchidectomy, which is often performed in this condition.

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Myriam Rosilio, Jean-Claude Carel, Emmanuel Ecosse and Jean-Louis Chaussainon

Group-author : on behalf of the 0908 Lilly Study Group

Objective: Human GH (hGH) treatment leads to catch-up growth in children with short stature born small for gestational age (SGA). However, long-term efficacy and safety results in this patient group remain scarce. The present study assessed the efficacy and safety of late childhood treatment with biosynthetic hGH (Humatrope) in a group of short children born SGA (height <−2 standard deviation scores (SDS)).

Design: Patients in this open-label, Phase III, multicenter study received a daily hGH dose of 0.067 mg/kg for 2 years, and then received no treatment for the following 2 years. After the fourth year on study, patients whose height had decreased more than 0.5 SDS but who still showed growth potential based on bone age were allowed to resume treatment until they reached adult height.

Methods: Height gain SDS was assessed for 11 girls and 24 boys (mean age±s.d. 9.6±0.9 years) at the end of the 2 years of hGH treatment, during the subsequent 2-year off-treatment period, and upon reaching adult height.

Results: At the end of the initial 2-year treatment period, 83% of patients had reached a height within the normal range, with a mean increase in height SDS vs baseline of 1.3±0.3 (P <0.001). Adult heights (n = 20) were within the normal range for 50% of patients, and mean height gain from baseline was statistically significant (0.7±0.8 SDS, P <0.001). Fasting glucose and glycosylated hemoglobin levels were not significantly modified during treatment.

Conclusions: High-dose hGH treatment for a minimum of 2 years in short children born SGA was well tolerated and resulted in a significant increase in adolescent and adult height.

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Maritza Vivanco, Jean-Hugues Dalle, Corinne Alberti, Brigitte Lescoeur, Karima Yakouben, Jean-Claude Carel, André Baruchel and Juliane Léger


The risk of radiation-induced benign and malignant thyroid nodules is well known.


The aim of this study was to determine the occurrence of thyroid nodules and carcinomas after fractionated total body irradiation (TBI) preceding hematopoietic stem cell transplantation (HSCT) for malignant hematological disease during childhood.


We conducted a retrospective university hospital-based observational study. The participants were 76 patients receiving fractionated TBI between 1989 and 2009 as part of the conditioning regimen for HSCT to treat malignant hematological disease, with a median age of 8.2 (5.7–11.4) years, for whom the last ultrasound examination was performed at a median age of 14.2 (11.2–17) years. The main outcome measure was cumulative incidence of thyroid nodules detected by ultrasound scans followed by biopsy if necessary.


Thyroid nodules were examined in 21 (28%) patients, six (29%) of whom were diagnosed with thyroid carcinoma at the age of 2.2–18.6 years after TBI. The cumulative incidence of nodule occurrence increased with increasing time from diagnosis. The 10-year cumulative incidence of benign and malignant thyroid nodules was 16% (95% confidence interval (CI) 4–27%) and 8% (95% CI 0–16%) respectively. Seventeen (22%) patients had hypothyroidism (compensated n=12, in five patients it was transient). No significant independent risk factors were identified in the multivariable competing risk model as a function of nodule occurrence.


Short-term and life-long monitoring, with screening for nodules of the thyroid gland using ultrasound scans, is recommended for survivors subjected to TBI for HSCT during childhood.

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Thomas Blanc, Ahmed Ayedi, Alaa El-Ghoneimi, Hendy Abdoul, Yves Aigrain, Françoise Paris, Charles Sultan, Jean-Claude Carel and Juliane Léger


There are few studies of outcome in male patients with undefined 46 XY disorder of sex development (DSD). We aimed to assess testicular function and clinical characteristics after puberty in men with idiopathic 46 XY DSD.


We conducted a University Hospital-based observational follow-up study.


Nineteen patients with severe hypospadias associated with other signs of defective virilization, such as microphallus, cryptorchidism, and/or bifid scrotum, who were initially managed during childhood between 1988 and 1994, were evaluated at a median age of 17.6 (16.3; 17.8) years. Outcome measures included clinical findings and serum testosterone, FSH, LH, and inhibin B concentrations.


Testicular function was normal in only five (26%) patients. Impaired testicular function was observed in 14 (74%) patients and was partial (n=6; 32%) or total (n=8; 42%), requiring testosterone treatment for the initial (n=2) or secondary (n=6) induction of puberty. Undescended testis (unilateral n=3, bilateral n=2) was found and surgically managed only in the 14 patients with testicular impairment. Testosterone treatment in early childhood greatly increased penis length in all patients, but persistent microphallus following surgical treatment was observed at the end of puberty in most patients, with no difference between patients with and without testicular dysfunction (penis length of 68 (60; 75) vs 65 (60; 65) mm; P=0.42). Half the patients presented an adult height more than 5 cm below their target height.


Men diagnosed with idiopathic 46 XY DSD during childhood are at high risk of testicular insufficiency and persistent micropenis, and this should be taken into account during the follow-up.

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Joëlle Le Moal, Annabel Rigou, Alain Le Tertre, Perrine De Crouy-Channel, Juliane Léger and Jean-Claude Carel


Precocious puberty seems to be increasing but epidemiological data are scarce. Our objective was to improve the epidemiologic knowledge on this disease. We analyzed the national incidence and spatial trends of idiopathic central precocious puberty in France in 2011–2013 in a cross-sectional descriptive study.


We used an indicator based on treatment reimbursements recorded in the national insurance database, in girls under the age of nine years and in boys under the age of 10 years. We considered a time lag of up to one year from the onset of puberty to first drug delivery. We tested four different predictive spatial models at the département scale, selecting the model best fitting the data. We carried out semi-structured interviews with qualified hospital teams in five selected regions to investigate spatial differences in medical practices.


The national annual incidence was 2.68 (95% CI: 2.55, 2.81) per 10 000 girls under the age of 9 years and 0.24 (95% CI: 0.21, 0.27) per 10 000 boys under the age of 10 years. Incidence rates conformed to a purely spatial heterogeneity model in girls, consistent between age groups, with a large incidence range. A similar pattern was observed for boys, with peaks in the South West and Center East. Differences in medical practices may have slightly affected incidence locally, but could not entirely explain the marked geographic pattern.


The results suggest that the risk factors are similar for boys and girls and justify further investigations of the role of the environment.

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Jean-Claude Carel, Joëlle Blumberg, Christine Seymour, Catherine Adamsbaum and Najiba Lahlou

Group-author : for the Triptorelin 3-month CPP Study Group

Objective: Depot GnRH agonists are commonly used in the treatment of central precocious puberty (CPP). The triptorelin 11.25 mg 3-month depot, currently used in adult indications, had not previously been evaluated in CPP.

Design: This was a multicenter, open-label, 12 month trial conducted in 64 CPP children (54 girls and 10 boys), treated quarterly.

Methods: Children with a clinical onset of pubertal development before the age of 8 years (girls) or 9 years (boys), pubertal response of LH to GnRH ≥7 IU/l, advanced bone age >1 year, enlarged uterus (≥36 mm) and testosterone level ≥0.5 ng/ml (boys), were included. Suppression of gonadotropic activation, as determined from serum LH, FSH, estradiol or testosterone, and pubertal signs were assessed at Months 3, 6 and 12.

Results: GnRH-stimulated peak LH ≤3 IU/l, the main efficacy criterion, was met in 53 out of 62 (85%), 60 out of 62 (97%) and 56 out of 59 (95%) of the children at Months 3, 6 and 12 respectively. Serum FSH and sex steroids were also significantly reduced, while pubertal development regressed in most patients. Mean residual triptorelin levels were stable from Month 3 through to Month 12. The triptorelin 3-month depot was well tolerated. Severe injection pain was experienced in only one instance. Five girls experienced mild-to-moderate or severe (one girl) withdrawal bleeding.

Conclusions: The triptorelin 3-month depot efficiently suppresses the pituitary–gonadal axis and pubertal development in children with CPP. This formulation allows a 3-fold reduction, over the once-a-month depot, in the number of i.m. injections required each year.

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Jean-Claude Carel, Najiba Lahlou, Laura Guazzarotti, Maryse Joubert-Collin, Marc Roger, Michel Colle, The French Leuprorelin Trial Group and Jean Louis Chaussain

Carel J-C, Lahlou N, Guazzarotti L, Joubert-Collin M, Roger M. Colle M, The French Leuprorelin Trial Group, Chaussain JL. Treatment of central precocious puberty with depot leuprorelin. Eur J Endocrinol 1995;132:699–704. ISSN 0804–4643

We evaluated the pituitary and gonadal suppression in 40 girls and nine boys treated with depot leuprorelin (3.75 mg sc if body weight ≥20kg, 1.87 mg if body weight <20 kg) every 28 days for central precocious puberty. Gonadal suppression was obtained in most of the children with this dose: 3 months after initiation of the treatment, 85% of children had a peak plasma luteinizing hormone response to gonadotropin-releasing hormone <3 IU/l and the gonadal axis remained suppressed throughout the duration of the study (up to 24 months). Four patients required higher doses of leuprorelin to achieve suppression. In two girls, a cutaneous reaction to the drug was associated with incomplete suppression and the treatment had to be interrupted. Plasma leuprorelin levels tended to increase from day 3 to day 28 after injection. Residual leuprorelin levels measured 28 days after injection were stable during the first year of the study. We conclude that an initial dose of depot leuprorelin of 3.75 mg sc every 28 days is efficient in most children with central precocious puberty.

Jean-Claude Carel, INSERM U342, Hôpital Saint Vincent de Paul, 82 av Denfert Rochereau, 75014 Paris, France

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Selmen Wannes, Monique Elmaleh-Bergès, Dominique Simon, Delphine Zénaty, Laetitia Martinerie, Caroline Storey, Georges Gelwane, Anne Paulsen, Emmanuel Ecosse, Nicolas De Roux, Jean Claude Carel and Juliane Léger


Non-idiopathic CPP is caused by acquired or congenital hypothalamic lesions visible on MRI or is associated with various complex genetic and/or syndromic disorders. This study investigated the different types and prevalence of non-isolated CPP phenotypes.

Design and Methods

This observational cohort study included all patients identified as having non-idiopathic CPP in the database of a single academic pediatric care center over a period of 11.5 years. Patients were classified on the basis of MRI findings for the CNS as having either hypothalamic lesions or complex syndromic phenotypes without structural lesions of the hypothalamus.


In total, 63 consecutive children (42 girls and 21 boys) with non-isolated CPP were identified. Diverse diseases were detected, and the hypothalamic lesions visible on MRI (n = 28, 45% of cases) included hamartomas (n = 17; either isolated or with an associated syndromic phenotype), optic gliomas (n = 8; with or without neurofibromatosis type 1), malformations (n = 3) with interhypothalamic adhesions (n = 2; isolated or associated with syndromic CNS midline abnormalities, such as optic nerve hypoplasia, ectopic posterior pituitary) or arachnoid cysts (n = 1). The patients with non-structural hypothalamic lesions (n = 35, 55% of cases) had narcolepsy (n = 9), RASopathies (n = 4), encephalopathy or autism spectrum disorders with or without chromosomal abnormalities (n = 15) and other complex syndromic disorders (n = 7).


Our findings suggest that a large proportion (55%) of patients with non-isolated probable non-idiopathic CPP may have complex disorders without structural hypothalamic lesions on MRI. Future studies should explore the pathophysiological relevance of the mechanisms underlying CPP in these disorders.