Michel Polak

Objective: To investigate the effect of age at growth hormone (GH) treatment start on near adult height (NAH) in children with isolated GH deficiency (GHD).Design: NordiNet® International Outcome Study (IOS) (Nbib960128), a non-interventional, multicentre study, evaluates the long-term effectiveness and safety of Norditropin® (somatropin) (Novo Nordisk A/S) in the real-life clinical setting.Methods: Patients (n = 172) treated to NAH (height at ≥18 years, or height velocity 11)) and GHD severity (n = 40 (boys, 70.0%); least squares mean (standard error) −0.76 (0.14)) exceeded that achieved by those starting later (intermediate,n = 42 (boys, 57.1%); −1.14 (0.15); late,n = 90 (boys, 68.9%); −1.21 (0.10)). Multiple regression analysis showed a significant association between NAH SDS and age at treatment start (P < 0.0242), baseline height SDS (HSDS) (P < 0.0001), target HSDS (P < 0.0001), and GHD severity (P = 0.0012). Most (78.5%) patients achieved a normal NAH irrespective of age at treatment start.Conclusions: Early initiation of GH treatment in children with isolated GHD improves their chance of achieving their genetic height potential.

Aims: The BRAFV600E oncogene, reported in 40-60% of papillary thyroid carcinoma (PTC), has an important role in the pathogenesis of PTC. It is associated with the loss of thyroid iodide-metabolizing genes, such as sodium/iodide symporter (NIS) and therefore with radioiodide-refractoriness. Inhibition of MAPK pathway, constitutively activated by BRAFV600E, is not always efficient in resistant tumors suggesting that other compensatory mechanisms contribute to a BRAFV600E adaptive resistance. Recent studies pointed to a key role of TGF-β in BRAFV600E-induced effects. The reactive oxygene species (ROS)-generating NADPH oxidase NOX4, which is increased in PTC, has been identified as a new key effector of TGF-β in cancer, suggestive of a potential role in BRAFV600E-induced thyroid tumors. Results: Here, using two human BRAFV600E mutated thyroid cell lines and a rat thyroid cell line expressing BRAFV600E in a conditional manner we show that NOX4 up-regulation is controlled at the transcriptional level by the oncogene via the TGF-β/Smad3 signaling pathway. Importantly, treatment of cells with NOX4-targeted siRNA downregulates BRAFV600E-induced NIS repression. Innovation and Conclusion: Our results establish a link between BRAFV600E and NOX4, which is confirmed by a comparative analysis of NOX4 expression in human (TCGA) and mouse thyroid cancers. Remarkably, analysis of human and murine BRAFV600E-mutated thyroid tumors highlights that the level of NOX4 expression is inversely correlated to thyroid differentiation suggesting that other genes involved in thyroid differentiation in addition to NIS might be silenced by a mechanism controlled by NOX4-derived ROS. This study opens a new opportunity to optimize thyroid cancer therapy

We would like to respond to the comment made by Beltrand et al. (1). In our study (2), we hypothesized that a successful switch from insulin to sulfonylurea therapy in patients with neonatal diabetes owing to KATP channel mutations would improve neurodevelopmental parameters. It was a prospective single-center cohort study of patients switched from insulin to sulfonylurea therapy. The inclusion criterion was neonatal diabetes owing to a mutation in the KCNJ11 or ABCC8 gene. We did not anticipate the neuropsychological changes …

OBJECTIVE: Neonatal diabetes secondary to mutations in potassium-channel subunits is a rare disease but constitutes a paradigm for personalized genetics-based medicine, as replacing the historical treatment with insulin injections with oral sulfonylurea (SU) therapy has been proven beneficial. SU receptors are widely expressed in the brain, and we therefore evaluated potential effects of SU on neurodevelopmental parameters, which are known to be unresponsive to insulin. RESEARCH DESIGN AND METHODS: We conducted a prospective single-center study. Nineteen patients (15 boys aged 0.1–18.5 years) were switched from insulin to SU therapy. MRI was performed at baseline. Before and 6 or 12 months after the switch, patients underwent quantitative neurological and developmental assessments and electrophysiological nerve and muscle testing. RESULTS: At baseline, hypotonia, deficiencies in gesture conception or realization, and attention disorders were common. SU improved HbA1c levels (median change −1.55% [range −3.8 to 0.1]; P < 0.0001), intelligence scores, hypotonia (in 12 of 15 patients), visual attention deficits (in 10 of 13 patients), gross and fine motor skills (in all patients younger than 4 years old), and gesture conception and realization (in 5 of 8 older patients). Electrophysiological muscle and nerve tests were normal. Cerebral MRI at baseline showed lesions in 12 patients, suggesting that the impairments were central in origin. CONCLUSIONS: SU therapy in neonatal diabetes secondary to mutations in potassium-channel subunits produces measurable improvements in neuropsychomotor impairments, which are greater in younger patients. An early genetic diagnosis should always be made, allowing for a rapid switch to SU.

Many clinical problems in the field of thyroid disease in paediatric patients remain unresolved. Therefore, the 2015 ‘special topic issue' of Hormone Research in Paediatrics focuses on new developments and new knowledge in this field, and some of the papers selected will add new insights while others provide new hypotheses.

Objective: To evaluate the prevalence of growth disorders and obesity in schoolchildren and determine whether school health check-ups are effective in their screening. Subjects-methods: Analysis of anonymized growth and body mass index (BMI) data from 2887 children attending the 3rd grade from 2008 to 2009 after selection of 75 elementary schools in Paris. Results: Linear growth velocity was abnormal in 198 children. Height and weight were above the French reference values (+0.9±1.2 SD and +1±1.7 SD, respectively). BMI was higher, compared to reference values (+0.4±1.4 SD). At their last check-up, 20.9% of children had a BMI>+2 SD. Conclusions: School health check-ups constitute a good screening tool for growth and obesity. However, further work is needed to determine the most effective modality. The reference values currently used in France are no longer suitable and new reference charts need to be established. The high prevalence of obesity in schoolchildren remains a public health challenge.

Background: Patients with brain tumours have a high risk of water and electrolyte disorders (WED). Postsurgery diabetes insipidus (DI) may be transient or permanent, the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and cerebral salt-wasting syndrome (CSWS) are usually transient. Methods: Retrospective study, including patients with suprasellar tumours, treated at Hôpital Necker, Institut Gustave-Roussy or Institut Curie, in Île-de-France, between 2007 and 2011. WED were noted if they persisted >1 month after surgery. Results: 159 patients were included, 54.1% girls, 43.9% boys. Tumour types were: glioma (43.4%), craniopharyngioma (43.4%), germinoma (11.3%), others (1.9%). Age at diagnosis was 7.1 ± 4.6 years. The median time from end of treatment was 1.9 (0-7.8) years. DI was the most frequent disorder after tumour treatment (50.3%) and was significantly associated with surgery (p < 0.001). Persistent CSWS was present in 3.6%, persistent SIADH in 1.3%. Two cases of hypernatraemia were due to adipsia. Thyrotropin deficiency after treatment was noted in 68.9% of patients tested, adrenocorticotropin deficiency in 66.2%. Conclusions: Patients with suprasellar tumours have a high incidence of long-term WED, mainly DI. Assessment of thyrotroph and corticotroph function, and thirst sensation, is necessary to diagnose and manage these disorders correctly. CSWS may be persistent in few patients and requires special attention to prescribe the appropriate care.

Context: Within the last two decades, heterozygous loss-of-function PAX8 mutations have been reported in patients with a wide degree of thyroid gland dysfunction and growth despite the presence of identical mutations.Objectives: To search for PAX8 mutations in a cohort of patients with congenital hypothyroidism (CH) and various types of thyroid gland defects.Design: A cross-sectional study was conducted in a cohort of patients.Setting: The French neonatal screening program was used for recruiting patients.Patients: A total of 118 patients with CH, including 45 with familial and 73 with sporadic diseases, were included in this study. The thyroid gland was normal in 23 patients had hypoplasia, 25 had hemithyroid agenesis, 21 had athyreosis, and 21 had ectopy.Results: We found four different PAX8 mutations (p.R31C, p.R31H, p.R108X, and p.I47T) in ten patients (six patients with CH and four family members), two with sporadic and eight with familial diseases. Imaging studies performed in the index cases showed ectopic thyroid gland (n=2), hypoplasia (n=2), eutopic lobar asymmetry (n=1), and eutopic gland compatible with dyshormonogenesis (n=1). The previously reported p.R31C and the novel p.I47T PAX8 mutations are devoid of activity.Conclusion: Four different PAX8 mutations were detected in six index patients with CH (ten total subjects). The p.R31C, p.R31H, and p.R108X mutations have been reported. The novel p.I47T PAX8 mutation presented loss of function leading to CH. Thyroid ectopy was observed in two cases of PAX8 (p.R31H) mutation, a finding that has not been reported previously. We observed a high inter-individual and intra-familial variability of the phenotype in PAX8 mutations, underlining that population genetic studies for CH should include patients with various clinical presentations.

Objective: Hyperthyroidism in neonates born to mothers with Graves' disease (GD) can be associated with significant morbidity and mortality, but is still overlooked by clinicians. Management of neonatal hyperthyroidism would be improved by a better understanding of the predictive factors involved. The aim of this study was to evaluate the course of thyroid function and clinical outcomes during the first postnatal month in babies born to mothers with GD.Design: Prospective observational study.Methods: Sixty-eight neonates born to mothers with GD were managed from birth and divided into three groups based on thyrotropin receptor antibody (TRAb) and anti-thyroid drug (ATD) status in the mother: TRAb^−ve/ATD^−ve,n=27; TRAb^−ve/ATD^+ve,n=8; and TRAb^+ve/ATD^+ve,n=33. The main outcome measures were clinical examination, thyroid function tests (TSH, free thyroxine (FT₄), free triiodothyronine, and TRAb), echocardiography, thyroid ultrasonography, and bone maturation assessment.Results: None of the infants born to TRAb^−vemothers with GD developed neonatal hyperthyroidism. Of the 33 TRAb^+ve/ATD^+veneonates, 24 (72.7%) had positive TRAb on cord blood assays, and seven of these developed neonatal hyperthyroidism. FT₄elevation between days 3 and 7 but not at birth was predictive of the development of hyperthyroidism.Conclusions: TRAb status should be checked in the third trimester in mothers with GD and on cord blood in their neonates; if positive, it indicates a high risk of neonatal hyperthyroidism. FT₄measurement at birth should be repeated between days 3 and 5 (and by day 7 at the latest); rapid FT₄elevation during the first postnatal week is predictive of hyperthyroidism and warrants ATD therapy.

Objective: The prevalence of severe primary IGF1 deficiency (IGFD) is unclear. IGFD must be identified promptly as treatment with recombinant human IGF1 (rhIGF1) is now available. Our objective was to characterize and assess the prevalence of severe primary IGFD in a large cohort of patients evaluated for short stature at a pediatric endocrinology unit in France.Design: Observational study in a prospective cohort.Methods: Consecutive patients referred to our unit between 2004 and 2009 for suspected slow statural growth were included. Patients were classified into eight etiological categories. IGFD was defined by height ≤−3 SDS, serum IGF1 levels <2.5th percentile, GH sufficiency, and absence of causes of secondary IGFD.Results: Out of 2546 patients included, 337 (13.5%) were born small for gestational age and 424 (16.9%) had idiopathic short stature. In these two categories, we identified 30 patients who met our criterion for IGFD (30/2546, 1.2%). In these 30 patients, we assessed the response to IGF1 generation test, time course of IGF1 levels, and efficiency of GH replacement therapy. The results indicated that only four of the 30 children were definite or possible candidates for rhIGF1 replacement therapy.Conclusion: The prevalence of severe primary IGFD defined using the standard criterion for rhIGF1 treatment was 1.2%, and only 0.2% of patients were eligible for rhIGF1 therapy.