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Jiska S Peper, Rachel M Brouwer, G Caroline M van Baal, Hugo G Schnack, Marieke van Leeuwen, Dorret I Boomsma, René S Kahn, and Hilleke E Hulshoff Pol


Brain volume of boys is larger than that of girls by ∼10%. Prenatal exposure to testosterone has been suggested in the masculinization of the brain. For example, in litter-bearing mammals intrauterine position increases prenatal testosterone exposure through adjacent male fetuses, resulting in masculinization of brain morphology.


The influence of intrauterine presence of a male co-twin on masculinization of human brain volume was studied in 9-year old twins.


Magnetic resonance imaging brain scans, current testosterone, and estradiol levels were acquired from four groups of dizygotic (DZ) twins: boys from same-sex twin-pairs (SSM), boys from opposite-sex twin-pairs (OSM), girls from opposite-sex twin-pairs (OSF), and girls from same-sex twin-pairs (SSF; n=119 individuals). Data on total brain, cerebellum, gray and white matter volumes were examined.


Irrespective of their own sex, children with a male co-twin as compared to children with a female co-twin had larger total brain (+2.5%) and cerebellum (+5.5%) volumes. SSM, purportedly exposed to the highest prenatal testosterone levels, were found to have the largest volumes, followed by OSM, OSF and SSF children. Birth weight partly explained the effect on brain volumes. Current testosterone and estradiol levels did not account for the volumetric brain differences. However, the effects observed in children did not replicate in adult twins.


Our study indicates that sharing the uterus with a DZ twin brother increases total brain volume in 9-year olds. The effect may be transient and limited to a critical period in childhood.

Free access

D Zenaty, Y Aigrain, M Peuchmaur, P Philippe-Chomette, C Baumann, F Cornelis, J P Hugot, D Chevenne, V Barbu, P J Guillausseau, M Schlumberger, J C Carel, J P Travagli, and J Léger


Early prophylactic thyroidectomy in patients with multiple endocrine neoplasia (MEN) type 2 offers the best chance for a normal life expectancy.


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.


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.


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.

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Gabriel Á Martos-Moreno, Vicente Barrios, and Jesús Argente

Objectives: To investigate the circulating levels of adiponectin, resistin, interleukin 6 (IL-6), and leptin/receptor ratio in healthy Spanish children throughout the different stages of pubertal development. To analyze the relationship between adipokines and sex steroid level changes during puberty.

Study design: Serum adiponectin, resistin, IL-6 levels, and leptin/receptor ratio were studied in 160 healthy Spanish children grouped according to their pubertal stage (Tanner I, 23 girls and 22 boys; Tanner II, 19 girls and 16 boys; Tanners III and IV, 21 girls and 20 boys; and Tanner V, 20 girls and 19 boys). In addition, circulating levels of sex hormone-binding globulin (SHBG) were determined in every subject, and testosterone and estradiol levels in boys and girls respectively.

Results: Adiponectin levels decreased in boys from mid puberty (P < 0.05) to become significantly lower than in girls (P < 0.001), whereas IL-6 decreased in both sexes (P < 0.05). Resistin levels and leptin/receptor ratio showed no differences between sexes or according to pubertal stage, except in adult females, who had the highest levels of both parameters (P < 0.001). Serum IL-6 levels correlated significantly (P < 0.05) with testosterone and estradiol levels (r=−0.37 and −0.42 respectively), whereas estradiol, but not testosterone, correlated with leptin/receptor ratio (r=0.59; P < 0.001). Furthermore, a positive relationship was found between SHBG and adiponectin and IL-6 (P < 0.001 and P < 0.05 respectively). In addition, a direct correlation between leptin/receptor and body mass index was found in both sexes (P < 0.001).

Conclusion: Variations in adipokine profiles throughout pubertal development appear to be related with progression of gonadal function.

Free access

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.

Free access

G E Krassas, M Segni, and W M Wiersinga

Objective: Evaluation of the frequency of Graves’ ophthalmopathy (GO) and its management in children and adolescents up to 18 years old with Graves’ hyperthyroidism.

Study design: This was a questionnaire study (QS) among members of the European Thyroid Association and the European Society for Paediatric Endocrinology. Approximately 300 QS were sent to members with electronic addresses and 110 QS were returned from 25 countries: 52 respondents said they had no experience with Graves’ disease in this age group, but 67 respondents (23 paediatric and 44 adult endocrinologists) completed the QS.

Results: Out of 1963 patients with juvenile Graves’ hyperthyroidism seen by respondents in the last 10 years, 641 (33%) had GO; about one-third of GO cases were ≤10 years old, and two-thirds were 11–18 years old. The prevalences of GO among juvenile Graves’ hyperthyroidism were 36.6, 27.3 and 25.9% in countries in which the smoking prevalence among teenagers was ≥25, 20–25 and <20% respectively (P < 0.0001 by χ2 test). When confronted with the standard case of a 13-year-old girl with Graves’ hyperthyroidism and moderately severe active GO, the diagnostic approach included on average 4.9 biochemical tests (TSH, free thyroxine (FT4) and TSH.R-Ab, 100-88% of respondents) and 2.4 specific investigations (thyroid ultrasound by 69%, orthopsy/visual fields/visual acuity by 64% and orbital magnetic resonance imaging or computed tomography by 63%). Antithyroid drugs were the treatment of choice for 94% of respondents; 70% recommended a wait-and-see policy and 28% corticosteroids for the co-existing GO. In variants of the standard case, a younger age did not affect therapeutic approach very much. Recurrent hyperthyroidism would still be treated with antithyroid drugs by 66%, and with 131I by 25%. Worsening of GO or active GO when euthyroid would convince about two-thirds of respondents to initiate treatment of GO, preferably with steroids.

Conclusion: GO occurs in 33% of patients with juvenile Graves’ hyperthyroidism; its prevalence is higher in countries with a higher prevalence of smoking among teenagers. The diagnostic approach to the standard case of a 13-year-old with Graves’ hyperthyroidism and moderately severe active GO involves on average five biochemical tests; thyroid as well as orbital imaging is done in 84% of cases. Antithyroid drugs remain the treatment of choice for 94% of respondents, and even so in case of recurrences (66%). For GO, 70% recommend a wait-and-see policy; intervention, preferably with steroids, is advocated by two-thirds of respondents in cases of worsening or still-active eye disease despite euthyroidism.

Free access

Felix G Riepe, Wiebke Ahrens, Nils Krone, Regina Fölster-Holst, Jochen Brasch, Wolfgang G Sippell, Olaf Hiort, and Carl-Joachim Partsch

Objective: To clarify the molecular defect for the clinical finding of congenital hypothyroidism combined with the manifestation of calcinosis cutis in infancy.

Case report: The male patient presented with moderately elevated blood thyrotropin levels at neonatal screening combined with slightly decreased plasma thyroxine and tri-iodothyronine concentrations, necessitating thyroid hormone substitution 2 weeks after birth. At the age of 7 months calcinosis cutis was seen and the patient underwent further investigation. Typical features of Albright’s hereditary osteodystrophy (AHO), including round face, obesity and delayed psychomotor development, were found.

Methods and results: Laboratory investigation revealed a resistance to parathyroid hormone (PTH) with highly elevated PTH levels and a reduction in adenylyl cyclase-stimulating protein (Gsα) activity leading to the diagnosis of pseudohypoparathyroidism type Ia (PHP Ia). A novel heterozygous mutation (c364T > G in exon 5, leading to the amino acid substitution Ile-106 → Ser) was detected in the GNAS gene of the patient. This mutation was not found in the patient’s parents, both of whom showed normal Gsα protein activity in erythrocytes and no features of AHO. A de novo mutation is therefore likely.

Conclusions: Subcutaneous calcifications in infancy should prompt the clinician to a thorough search for an underlying disease. The possibility of AHO and PHP Ia should be considered in children with hypothyroidism and calcinosis cutis. Systematic reviews regarding the frequency of calcinosis in AHO are warranted.

Free access

L Lazar, U Pollak, O Kalter-Leibovici, A Pertzelan, and M Phillip

OBJECTIVE: Few data are available on the pubertal development of children born small for gestational age (SGA) who fail to show catch-up growth. DESIGN: A longitudinal analysis compared the pubertal course of persistently short children born SGA compared to children with idiopathic short stature who were appropriate for gestational age (AGA). One hundred and twenty-eight short children (height SDS<-1.7), including 76 (31 boys) born SGA and 52 (22 boys) born AGA, were regularly followed from early childhood to completion of puberty. RESULTS: Puberty was attained at normal age (10.5-14 Years in boys, 9.5-13 Years in girls) for most children in both the SGA and AGA groups (boys, 80% and 77%; girls, 76% and 78% respectively). The duration of puberty was similar in the SGA and AGA groups. Menarche occurred at normal age range but was significantly earlier in the SGA girls (P<0.01 by ANOVA). Despite the similar total pubertal growth, the patterns of growth differed significantly: SGA group - accelerated growth and bone maturation rates from onset of puberty with peak height velocity at Tanner stages 2-3, followed by a decelerated growth rate and earlier fusion of the epiphyses; AGA group - steady progression of bone elongation and maturation throughout puberty (pubertal growth, P<0.05 in both sexes; bone maturation, P<0.001 in both sexes). Final height in the SGA group was compromised compared with their target height (P<0.001). CONCLUSION: Children born SGA have a normal pubertal course with a distinct pubertal growth pattern. This pattern may represent an altered regulation of their growth modalities.

Free access

Carla Bizzarri, Antonello E Rigamonti, Antonella Luce, Marco Cappa, Silvano G Cella, Jenny Berini, Alessandro Sartorio, Eugenio E Müller, and Alessandro Salvatoni

Background and aims

Ghrelin is an orexigenic 28-amino acid peptide produced by the stomach. Circulating ghrelin levels rise shortly before and fall shortly after every meal. Peptide YY (PYY), an anorexigenic 36-amino acid peptide, is secreted primarily from the intestinal mucosa of the ileum and large intestine. Plasma PYY levels begin to rise within 15 min after starting to eat and plateau within ∼90 min, remaining elevated for up to 6 h. Recently, some studies have tried to evaluate the potential role of ghrelin and PYY in the hyperphagia of patients with Prader–Willi syndrome (PWS). While hyperghrelinemia is well characterized in PWS, conflicting results have been reported for PYY. The aim of the study was to investigate ghrelin and PYY responses to a standard liquid high-fat meal in children with PWS.

Patients and methods

Circulating levels of total ghrelin and PYY levels were assayed by RIA after overnight fasting and 45, 60, 90, and 180 min following a standard meal (Ensure 6 ml/kg) in 16 patients with PWS (11 boys and five girls, aged 4.6–10.7 years, including ten receiving 0.02 mg/kg per day rhGH for 2–18 months; body mass index (BMI) z-score: 0.6±0.2 and 1.6±0.5 for children treated or not treated with rhGH respectively), ten obese (eight boys and two girls, aged 9.2–15.6 years; BMI z-score: 2.4±0.2, i.e. BMI >97th centile for chronological age and sex) subjects, and 16 normal-weight controls (five boys and 11 girls, aged 5.8–17.3 years; BMI z-score: 0.6±0.2).


PWS children showed higher fasting levels of ghrelin than obese and lean controls. Postprandial ghrelin drop was more pronounced in PWS than in the other study groups. No significant difference on fasting levels of PYY was found among groups. PWS showed a higher postprandial PYY rise than obese and lean controls. PWS patients treated and not treated with GH showed similar fasting and postprandial levels of ghrelin and PYY. Fasting PYY levels correlated negatively (P<0.05; r=−0.68) with those of ghrelin only in PWS.


The results of this study confirm fasting hyperghrelinemia in PWS. Since in PWS adults an impaired postprandial suppression of plasma ghrelin was previously reported to be associated with a blunted postprandial PYY response, the finding of a meal-induced decrease and increase in ghrelin and PYY levels respectively in PWS children would imply that the regulation of appetite/satiety of these peptides is operative during childhood, and it progressively deteriorates and vanishes in adulthood when hyperphagia and obesity worsen.

Free access

S A van Gool, G A Kamp, R J Odink, S M P F de Muinck Keizer-Schrama, H A Delemarre-van de Waal, W Oostdijk, and J M Wit


To assess the long-term effect of prepubertal high-dose GH treatment on growth in children with idiopathic short stature (ISS).

Design and methods

Forty children with no signs of puberty, age at start 4–8 years (girls) or 4–10 years (boys), height SDS <−2.0 SDS, and birth length >−2.0 SDS, were randomly allocated to receive GH at a dose of 2 mg/m2 per day (equivalent to 75 μg/kg per day at start and 64 μg/kg per day at stop) until the onset of puberty for at least 2 years (preceded by two 3-month periods of treatment with low or intermediate doses of GH separated by two washout periods of 3 months) or no treatment. In 28 cases, adult height (AH) was assessed at a mean (s.d.) age of 20.4 (2.3) years.


GH-treated children (mean treatment period on high-dose GH 2.3 years (range 1.2–5.0 years)) showed an increased mean height SDS at discontinuation of the treatment compared with the controls (−1.3 (0.8) SDS versus −2.6 (0.8) SDS respectively). However, bone maturation was significantly accelerated in the GH-treated group compared with the controls (1.6 (0.4) versus 1.0 (0.2) years per year, respectively), and pubertal onset tended to advance. After an untreated interval of 3–12 years, AH was −2.1 (0.7) and −1.9 (0.6) in the GH-treated and control groups respectively. Age was a positive predictor of adult height gain.


High-dose GH treatment restricted to the prepubertal period in young ISS children augments height gain during treatment, but accelerates bone maturation, resulting in a similar adult height compared with the untreated controls.

Free access

B Gyorffy, B Vasarhelyi, D Krikovszky, L Madacsy, A Tordai, T Tulassay, and A Szabo

OBJECTIVE: Recent data have indicated the significance of vitamin D receptor (VDR) polymorphisms in type 1 diabetes mellitus (T1DM). We have studied the association of five known restriction enzyme polymorphisms of the VDR gene in patients with T1DM. DESIGN AND METHODS: One hundred and seven children with T1DM (T1DM for 5 Years; age, 1-14 Years; boys/girls, 57/50; body mass index, 17.0+/-2.3 kg/m(2); haemoglobin A(Ic) (HbA(Ic)), 7.87+/-1.05) and 103 healthy subjects were enrolled. The VDR polymorphisms ApaI, BsmI, FokI, TaqI and Tru9I ("a", "b", "f", "t" and "u" alleles respectively) were investigated. RESULTS: The "t" and "T" alleles miss the Hardy-Weinberg equilibrium (P<0.01) in control and diabetic populations; we therefore excluded this polymorphism from further analysis. We did not find a difference in the allele prevalence in T1DM patients and controls of any of the five polymorphisms. However, when the "b", "a" and "u" alleles were simultaneously compared in girls, there was a significantly higher prevalence in patients with diabetes compared with controls ("b"+"a"+"u" present/absent: healthy, 0/53; diabetic, 13/37; P<0.005). In boys the prevalence of "b"+"a"+"u" genotype was similar in T1DM and controls. CONCLUSIONS: The impact of the "t" allele cannot be investigated in this study population. Not a single VDR polymorphism increases the susceptibility to T1DM. The common presence of the "b", "a" and "u" alleles greatly increases the probability of T1DM in girls.