Bridging Clinical Care and Basic Research

Abstract

On 22–25 September 2010, the Annual Meeting of the European Society for Paediatric Endocrinology (ESPE) was held in Prague (Czech Republic). A total of 3053 delegates from Europe and outside Europe (i.e., from the USA, Canada, East and West Asian countries, Australia, South America and Africa) registered for the meeting, making the Annual Meeting of ESPE 2010 the largest ever European pediatric endocrine meeting. ‘Bridging Clinical Care and Basic Research’ was the main focus of this meeting.

Keywords::

• pediatric endocrine meeting
• pediatric endocrinology

The program of the European Society for Paediatric Endocrinology (ESPE) [101] covered the entire spectrum of pediatric endocrine problems and was structured with six plenary lectures (‘G-Protein Coupled Receptors/Adrenal Diseases‘; ‘PROP1 and the Bridge to Krk’ [102]), 11 educational symposia (‘Bridging Clinical Care and Basic Research‘; Ovarian Development, Adrenals – ESPE/SLEP, β-cell, Thyroid; Diabetes Immunotherapy; IGFs and the Nervous System; Endocrine Perspectives of Environmental Endocrine Disruption; Diabetes in Europe – The SWEET project – ESPE/ISPAD; Epigenetics in Pediatric Endocrinology; New Developments in the Regulation of Puberty; Basis of Gender Identity: Implications for Disorders of Sex Development [DSD] Management – ESPE/ESPU), eight interactive meet-the-expert sessions (Central Diabetes Insipidus [M Magnie, University of Genova, Genova, Italy]; Long Term Follow-Up of Hashimoto Thyroiditis [M Niedziela, Poznan University of Medical Sciences, Poznan, Poland]; Precocious Puberty – When to Start and Stop Treatment [L Ghizzoni, University of Turin, Turin, Italy]; Type 2 Diabetes [S Arslanian, Weight Management and Wellness Center, Children’s Hospital of Pittsburgh, University Pittsburgh Medical Center, Pittsburgh, MA, US]; Interpretation of Endocrine Investigations in Complex DSD [Y Morel, Centre de Biologie et de Patologie, Hospices Civils de Lyon, Bron Cedex, France]; Late Effects, Endocrinopathies after Irradiation and Chemotherapy [C Kelnar, University of Edinburgh, Edinburgh, UK]; MRI in Congenital Hypopituitarism [CL Deal, CHU St-Justine and University of Montreal, Pediatrics, Montreal, Canada]; Management of Fetal Goitre [M Polak, Hôpital Necker Enfants Malades, Paris, France]; see handouts of these sessions at [103]), two new perspectives sessions (Towards the Future Cure of Diabetes, New Treatment Modalities for the Preservation of Fertility), free oral communications and poster presentations, meetings of ESPE Working Groups (Bone and Growth Plate; DSD; Obesity; Pediatric and Adolescent Gynecology; Turner Syndrome [TS]), and several satellite symposia sponsored by pharmaceutical companies.

Before the official opening of the meeting, there were parallel sessions of the ESPE Working Groups. DSD is one of these groups, currently realizing a collaborative project within the 7th Framework Programme and funded by the European Commission. This program, called EuroDSD [104], is a collaboration between doctors and scientists from all over Europe (Coordinator: O Hiort, University of Lubeck, Lubeck, Germany). The EuroDSD consortium consists of 13 European organizations. DSD constitutes a group of rare to very rare, mostly heritable, disorders affecting the genito–urinary tract and, in most instances, the endocrine–reproductive system. Long-term outcome studies on various DSD entities are desperately needed in order to establish a basis for evidence-based medicine regarding sex assignment, and conservative and surgical treatment options. In frame of the EuroDSD project, a total number of 702 patients from European centers were registered to date (R Sinnott, University of Glasgow, UK). Moreover, S Drop (Sophia Children’s Hospital/Erasmus MC, Rotterdam, The Netherlands) showed a new educational ESPE e-learning web portal [105]. P-M Holterhus (Schleswig-Holstein University, Kiel, Germany) demonstrated that apolipoprotein D is a potential biomarker of androgen receptor function in genital tissues, and could be used to establish the diagnosis of androgen-insensitivity syndrome (AIS). Apolipoprotein D response to DHT was extremely reduced or absent in all of their PAIS and CAIS samples, but was present in the 17β-HSDIII deficiency fibroblasts.

During the ESPE Study Group on TS meeting, the association between genetics and brain development was presented by DH Skuse (Institute of Child Health, London, UK) and AL Reiss (Stanford University School of Medicine, CA, USA). It is known that the X-chromosome plays a crucial role in the development of sexually selected characteristics. It has also been proven that X-linked genes are important for brain development and are strongly expressed in brain tissue. These genes influence mental function, intelligence, social cognition and emotional regulation. Sexually dimorphic processes can be influenced by several mechanisms, such as random X-linked gene inactivation, genomic imprinting and escape from X-inactivation. The origin of the X chromosome (maternal vs paternal) in TS is a deciding factor with regard to the social cognition differences seen between males and females. Studies show that girls with the paternal X chromosome are better adjusted, with superior verbal and higher-order executive function skills that mediate social interactions. This suggests that there is a genetic locus for social cognition that is imprinted and is not expressed from the maternal X chromosome. Genomic imprinting can be a mechanism by which X-linked genes are able to influence social cognition. X-linked genes and their expression are also able to modify phenotype. Monozygotic female twins are less similar than male monozygotic twins, probably owing to random inactivation of the X chromosome.

The working group on TS also presented the problem of androgen metabolism in TS (N Zuckerman-Levin, Meyer Children’s Hospital, Haifa, Israel). Gonadal dysgenesis in adolescent and adult TS is associated with reduced androgen levels by up to 50%. Adrenal androgens and adrenarche are normal in TS, and androgen deficiency develops with age. Androgen deficiency can have a negative influence on the functioning of women suffering from TS. It is suggested that morbidity associated with TS, such as bone fragility, metabolic changes, sexual problems and neurocognitive problems, may be related to androgen deficiency. Studies have demonstrated the effects of both estrogens and androgens on brain development. The cognitive maturation of TS is mostly dependent on X-linked genes, environmental factors and the hormonal status of the individual. Androgen-replacement therapy (ART) in TS is still under investigation. Studies have demonstrated that ART in TS patients has a beneficial effect on selective attention, and a decline on some parameters of sustained attention and executive functions. TS patients on ART have reported a significant improvement in quality of life.

During the TS satellite symposium, CA Bondy (National Institute of Child Health and Human Development, MD, USA) discussed transitional care in TS. Many adults with TS do not receive adequate medical supervision. The main practical indications for adult medical care are the following:

• Estrogen therapy is important, not only for breast development, but also for bone and uterus development;

• Bone-density studies are not needed until adult height is achieved and full estrogen therapy has been maintained for at least 1 year;

• Calcium and vitamin D supplementation (1000 IU/day) is recommended;

• Pregnancy in TS sufferers is associated with increased cardiovascular mortality;

• A healthy diet and regular exercise is advised;

• MRI is recommended for complete visualization of both ascending and descending aorta;

• Risk of aortic dissection is associated with bicuspid aortic valve, hypertension, webbed neck, pregnancy, absolute ascending aorta diameter over 3.5 cm, or a body surface area-adjusted measurement greater than 2.4 cm/m²;

• Regular hearing studies are also very important because hearing problems can lead to social isolation.

The symposium on IGF-1, the brain and the nervous system discussed new views on hormonal and neurological associations. M Holzenberger (Hôpital Saint-Antoine, Paris, France) discussed the role of brain IGF-1 receptors (IGF-1Rs) in aging. The studies presented demonstrated that aging is controlled by the somatotrophic axis. The reduced activity of the somatotrophic axis increases the lifespan of the individual. Studies in mice demonstrated that reduction of PROP1 [102], PIT1, GHRH receptor (GHRHR) and IGF-1R results in an increased lifespan. Caloric restriction decreases IGF-1 and insulin levels, and demonstrates the same effect. Studies with IGF-1R knockout mice demonstrated that approximately 20% of lifespan variation is determined by IGF-1R in the brain by influencing the activity of pituitary GHRHR.

A Musaro (Sapienza University of Rome, Rome, Italy) presented the possible therapeutic role of IGF-1 in neuromuscular disease. The IGF-1 gene encodes different protein isoforms, each playing a different role within the same tissue in which they are expressed. There is a locally generated form acting in a paracrine way and the liver generated circulating form acting in a systemic way. The local form of IGF-1 (mIGF-1) contains Ea peptides and has been shown to increase muscular force and mass. The studies on mice with overexpressed mIGF-1 have demonstrated that mIGF-1 results in a preservation of muscle mass. It was also shown that mIGF-1 safely enhances and preserves muscle fiber integrity in aging and muscular dystrophy by reducing fibrosis and myonecrosis, and elevating signaling pathways associated with muscle survival and regeneration.

D Ley (Lund University, Lund, Sweden) discussed the role of IGF-1 in preterm neonate brain development. IGF-1 and IGFBP3 levels rise from 30 gestational weeks, but in preterm-born infants at the same gestational time the increase is not observed. IGF-1 levels correlate with reduced cerebellar volume, and reduced white and grey matter and total brain volume. Low IGF-1 at 30–34 gestational weeks in preterm deliveries is a good predictor of severe retinopathy. Therapy with combined IGF-1 and IGFBP3 in premature neonates has the potential to reduce retinopathy and positively affect brain development.

During the session on ‘Defects in the GH–IGF-1 Axis’, interesting information was presented. M McCabe et al. (Institute of Child Health, London, UK) aimed to investigate the role of FGF8 in the formation of mid-line forebrain and craniofacial structures in humans. A total of 600 patients with congenital hypopituitarism and mid-line forebrain/craniofacial defects were screened for mutations in FGF8. They demonstrated for the first time a recessive FGF8 mutation (p.R189H) in a patient with holoprosencephaly. The p.Q216E mutation was identified in a female with an absent corpus callosum and hypoplastic optic nerves, and suffering from Moebius syndrome. The data suggest a role for Fgf8/FGF8 in the forebrain and hypothalamic development of humans, suggesting an overlap in pathogenesis between Kallmann syndrome and complex midline defects with hypopituitarism.

WF Blum (Eli Lilly & Co., Bad Homburg, Germany) and coworkers presented ‘Screening of a large cohort of pediatric patients with GH deficiency for mutations in genes involved in the regulation of pituitary development and GH secretion’. A total of 709 patients were enrolled in this study. The following genes were screened for mutations: GH1, GHRHR, GLI2, HESX1, LHX3, LHX4, POU1F1, PROP1, SHH and SOX. Mutations were found in 10.9% of patients with isolated GH deficiency (IGHD). In a group of patients with multihormonal pituitary deficiency (MPHD), 18.4% of patients presented with a mutation. Interestingly, five patients with IGHD, two with PROP1 and three with GH1 mutations developed MPHD. In patients with MPHD, there was a regional clustering of PROP1 mutations in patients of Eastern Europe origin compared with those originating from Western Europe.

G Binder (University Children’s Hospital Tübingen, Tübingen, Germany) and coauthors presented a study on sound reference values and a diagnostic cut-off for growth hormone (GH) levels in newborns between days 3 and 5. GH was measured in the eluate from 314 filter papers of the newborn screening test performed in the hospital by using a highly sensitive human growth hormone (hGH)-ELISA test. In the presence of clinical evidence, the diagnosis of neonatal GHD can be confirmed during the first week of life by a single randomly evaluated GH level of less than 7 µg/l with 100% sensitivity and 98% specificity. The GH content in newborn screening cards stored for almost 3 years was not different to the content found in recently used screening cards, indicating high immunological stability of GH over time. This study provides a reliable approach for the diagnosis of severe GHD in the newborn.

J-M Wit (Leiden University Medical Center, Leiden, The Netherlands) and coworkers presented a study titled ‘Genetic analysis of primary IGF-I deficiency’ during the Growth Regulation session. In 29 patients sharing a height under -1.9 standard deviation score and a relatively low IGF-I for GH secretion mutation the genetic analysis of GH1, GHR, STAT5B, IGFALS and IGF1 was performed. In 24% of the patients DNA changes were found, but in most of them the impact on gene function was unclear. Even in a selected patient sample, pathogenic aberrations of known candidate genes were rare.

During the ESPE 2010 Meeting session discussing the prediction models for GH therapy response, it was suggested to include genotyping of the GH receptor (GHR) in the discussion [101]. Two of the most common isoforms of GHR in humans are generated by retention of exon 3 in the GHR transcript or its exclusion. These isoforms present a widespread distribution in humans. Subjects with exon 3 deleted from the GHR gene and with severe GHD had increased height velocity and greater adult height with hGH treatment. Patients with GHD who were homozygous for full-length GHR containing the part encoded by exon 3 were less responsive to short- and long-term hGH therapy.

Thyroid autoimmunity was widely discussed during the meeting, with special emphasis on fetal goiter, Hashimoto thyroiditis and childhood hyperthyroidism.

The ability of the thyroid-stimulating hormone receptor (TSHR) to respond to thyroid-stimulating hormone (TSH) stimulus is possible from the 20th week of gestation. After the 20th week of gestation, there is also a greater permeability of the placenta for TSHR antibodies (TRAbs) from the mother (with a history of Graves’ disease [GD]) to the fetus. Therefore, such fetuses are at increased high risk for the development of hyperthyroidism with goiter if mother is a carrier of these antibodies. Even though the radical treatment (total thyroidectomy or radioiodine thyroid ablation) was performed in a woman with GD several months or years before pregnancy there is still a risk that she carries high level TRAbs and may affect fetal/neonatal thyroid state. The measurement of TRAb allows prediction of the risk of goiter with hyperthyroidism. The first sign of fetal hyperthyroidism is the presence of goiter on ultrasound and fetal tachycardia is the second sign. Around the 30th week of gestation, the fetal TRAb level is equal to maternal TRAb. Fetal blood sampling should be considered only when fetal thyroid status (hypo- vs hyperthyroidism) cannot be inferred from echography, and if in utero treatment (intra-amniotic L-T4 injections) is considered (M Polak).

There is a wide spectrum of chronic autoimmune thyroiditis among children. The two major forms of the disorder are goitrous autoimmune thyroiditis and atrophic autoimmune thyroiditis (less common), with the most common pathologic feature being lymphocytic infiltration and the most common serological feature being the presence of high serum concentrations of antibodies to thyroid peroxidase (TPOAb) and thyroglobulin (TgAb). Therefore, the diagnosis of chronic immunologic thyroiditis should be made on the basis of either elevated titers of at least one of antithyroid antibodies (TgAb or TPOAb; seropositive patient; chronic autoimmune thyroiditis) and/or fine-needle-aspiration cytology (lymphocytic infiltration; chronic lymphocytic thyroiditis) of the thyroid gland. Unlike TgAb and TPOAb, which are commonly used as markers of underlying thyroid autoimmunity, TRAbs can mimic or block TSH-induced stimulation of thyroid growth and hormonogenesis. TSHR-blocking antibodies occur in at least 9.2% of children and adolescents with chronic autoimmune/lymphocytic thyroiditis patients, including children as young as 4 years of age, contributing significantly to the severity of the hypothyroidism in these patients and being unlikely to be found in those individuals whose serum TSH concentrations are less than 20 mU/l. These antibodies are particularly important in those with primary myxedema. The natural course of autoimmunity and changes in thyroid function over time is usually slow and unpredictable. The goals of treatment are prevention of progression to overt hypothyroidism by normalization of thyroid hormone and TSH levels, prevention of thyroid enlargement (or even reduction of thyroid volume) and nodule/cancer formation, and long-term screening for other autoimmune diseases. The treatment of choice is l-thyroxine (L-T4), since there is no cure for the disease. Questions arise as to when to start L-T4 treatment, and whether the disease might be reversible. Treatment with L-T4 in children with chronic autoimmune/lymphocytic thyroiditis is controversial and always recommended for children with overt hypothyroidism and the treatment should be individualized in euthyroid and subclinically hypothyroid patients (M Niedziela).

The treatment of hyperthyroidism (GD) is very challenging, and since the remission rate is very low, the more radical treatment modality should be advised (surgery or radioiodine). Methimazole is the drug of choice as the initial treatment. Propylthiouracil should no longer be used as an antithyroid drug in pediatric patients, since severe liver injury with a risk of death may occur. In the case of young children (<5 years) with severe orbitopathy, severely enlarged glands, low radioiodine uptake and the coexistence of thyroid nodules, thyroid surgery should be performed. Thyroidectomy is safe in experienced hands and also gives the chance for a decline of TRAb levels. By contrast, after radioiodine treatment the TRAb levels might persist and stay elevated for years, thus causing risk to future pregnancies. Choosing a treatment approach for childhood GD is often a difficult and highly personal decision (H Krude, Charité University Hospital, Berlin, Germany and S Rivkeess, Yale University School of Medicine, CT, USA).

The ‘adrenal’ was widely discussed during the symposium ‘Bridging Clinical Care and Basic Science’. Triple-A syndrome (AAAS) was the first subject in this session, which was presented by A Hübner (Technical University Dresden, Dresden, Germany). Hübner provided a new insight into the pathogenesis of AAAS, also known as Adrenal insufficiency–Achalasia–Alacrima or Allgrove syndrome. She summarized the characteristic clinical features in 215 patients, 58% of which had, surprisingly, all three As and 35% who had two As indications. Alacrima was the most common manifestation of the disease (93% of individuals) that presented in childhood, usually at birth. Two other symptoms, achalasia and adrenal insufficiency, were found in 86 and 75% of cases, respectively. Both symptoms were present at a mean age of approximately 7 years. The spectrum of neurological manifestation of AAAS is broad and includes inter alia progressive neurological degeneration and occasionally autonomic instability. AAAS is a complex and multisystemic, autosomal, and a very rare recessive congenital disease caused by mutations in the AAAS gene located on chromosome 12 and encoding for the alacrima achalasia adrenal insuffiency neurologic disorder (ALADIN) protein. ALADIN belongs to the family of tryptophan-aspartate repeat-containing proteins and localizes to nuclear pore complexes (NPCs) together with three other nuclear proteins, NDC1, NUP8 and NUP62, which are involved in protecting cells against oxidative stress. The function of the ALADIN protein is still poorly understood, but it is hypothesized that it plays an important role in RNA and (or) protein trafficking between the nucleus and cytoplasm. It is supposed that mutation in the ALADIN protein changes its cellular localization and leads to the excessive reactive oxidative species production responsible for DNA damage, neuron degeneration and progressive neurological disorders. If this hypothesis is validated, antioxidant drugs could be recommended as a valuable treatment of AAAS patients to prevent or slow down progression of the disease.

The next talk entitled ‘Childhood adrenocortical carcinomas and p53 mutations’ was given by AC Latronico (São Paulo University Medical School, São Paulo, Brazil). Adrenocortical tumors in children and adolescents are quite rare and they may occur together with signs of virilization alone, virilization with Cushing‘s syndrome (50 and 40%, respectively) or Cushing‘s syndrome alone. Silent adrenocortical tumors are very rare events. Usually, adrenocortical carcinomas appear in children under 4 years of age. These tumors can be associated with various endocrine neoplasia syndromes such as Li-Fraumeni, McCune Albright, MEN1, Carney Complex, as well as with with familial hyperaldosteronism or Beckwith–Widermann syndrome. In 50–80% of patients with adrenocortical carcinomas, germline mutations in p53 gene were found. The speaker described the relatively high incidence in Southeast Brazilian pediatric patients with sporadic adrenocortical tumors. She pointed out that as much as 78–97% of these cases had a founder mutation, p.Arg337His (R337H), in the tetramerization domain of the tumor-suppressor p53 protein. Bi-allelic inactivation of p53 due to the presence of a R337H mutation of p53, as well as loss of heterozygosity of the 17p13 locus containing the p53 gene (including loss of the whole chromosome 17) did not correlate with tumor aggressiveness in these adrenocortical tumors, but in the majority of such cases loss of heterozygosity is a strong predictor of malignancy in adults (85% of carcinomas and 30% of adenomas) making it a molecular marker of tumor malignancy.

In his lecture, entitled ‘PAPSS2 deficiency and adrenal hyperandrogenism’ (3´-phosphoadenosine 5´-phosphosulfate [PAPS] synthase [PAPSS]), J Idkowiak (University of Birmingham, Birmingham, UK) concentrated on the DHEA sulfation system, including PAPS as the sulfate donor formed by the activity of PAPSS2 (ATP sulfurylase and APS kinase), which is used by SULT2A1 (DHEA sulfotransferase) in the process of androgen production. He also discussed its critical role in clinical hyperandrogenism. DHEA is the crucial precursor of human sex steroids. After synthesis it becomes efficiently converted into active androgen or alternatively to its inactive sulfate ester DHEAS. SULT2A1 is responsible for DHEA conversion into DHEAS using PAPS as a substrate. In humans, PAPS is synthesized thanks to the activity of PAPSS2, which stands for ATP sulfurylase and APS kinase. The enzyme exists in two isoforms, one of which (i.e., PAPSS1) is ubiquitously expressed as opposed to PAPSS2, which is expressed only in the liver and adrenal glands. When the process of DHEA conversion into inactive DHEAS is blocked, more DHEA will undergo conversion into androstendion, and thus hyperandrogenism may occur. This block may be owing to the presence of an inactivating mutation in the PAPS synthase 2 (PAPSS2) gene. This mutation was detected in a female child who, at the age of 8, presented with exaggerated adrenarche, a bone age of 12 years, and who had elevated levels of DHEA, androstendion and testosterone. DHEAS level in this patient was undetectable, on the other hand, high levels of DHEA and active androgens were observed, suggesting disorders with DHEA sulfation pathway. Other manifestations included low adult height and polycystic ovary syndrome at the age of 13 years. The results of the studies by Idkowiak et al. indicated that DHEA sulfation may be considered to be a gatekeeper of androgen synthesis pathway that determines the amount of androgen precursors and their active forms as well. Thus, disorders of DHEA sulfation appear to be a novel and crucial mechanism underlying early-onset clinical hyperandrogenism.

One of the plenary sessions included ESPE Activities and Awards. The ESPE Young Investigator Award is presented to a young pediatrician from Europe based on her/his scientific publications in the field of pediatric endocrinology. This year the award was presented to M Cools (University Hospital Gent, Gent, Belgium) for her work on the molecular genetics of human sexual development with respect to dysgenetic and streak gonadal tissue in individuals with gonadal dysgenesis. She focused mainly on the crossroad between SOX9 and FOXL2 genes in the process of gonadal determination. The SOX9 transcription factor, together with SF1, regulates transcription of the anti-Muellerian hormone gene (AMH). In turn, forkhead transcription factor (FOXL2) plays a crucial role in ovarian development and function. Cools demonstrated that when SOX9 gene is expressed high enough to reach its threshold inducing autoregulatory systems in testis, it leads to the development of localized tissue. On the other hand, the predominance of FOXL2 expression leads to the development of the ovary. Studies of localized expression of SOX9 and FOXL2 showed that localised testicular and/or ovarian tissues structures, in fact were present in gonads previously considered as ‘streak gonads’ with no recognizable features.

In turn, the ESPE Hormone Research in Pediatrics Prize is given for ‘Best Original Paper’. This year T Eldar-Geva (Shaare Zedek Medical Center, Jerusalem, Israel) was awarded for her article entitled ‘Primary ovarian dysfunction contributes to the hypogonadism in women with Prader–Willi syndrome’. J Starzyk (Jagiellonian University, Krakow, Poland) was, in turn, given the Prize for ‘Best Novel Insights Paper’ for his article ‘Ovarian Hyperstimulation Syndrome in Newborns – a Case Presentation and Literature Review’.

Three ESPE Research full-time fellowships for 2010–2011 were also awarded. The beneficiaries were as follows: Y von der Zwan (Erasmus MC, Rotterdam, The Netherlands; ‘The role of WWOX and FHIT in normal gonadal development and gonadal mal-development in patients with disorders of sex development consequences for malignant transformation of germ cells’), CM Moya (Spanish National Research Council–Autonomous University of Madrid, Madrid, Spain; ‘Micro RNAs and human thyroid dysgenesis’) and O Nilsson (Karolinska University Hospital, Stockholm, Sweden; ‘replicative senescence of growth plate chondrocytes – mechanism and implication for longitudinal bone growth’).

The ESPE Research Award is given for researchers for their outstanding achievements in basic endocrine science or clinical pediatric endocrinology. This year it was presented to P Clayton (University of Manchester, Manchester, UK) for his work on the molecular genetics of growth disorders. In his lecture entitled ‘Disordered human growth: from the GH Axis to ubiquitination’, he concentrated on growth hormone signaling through the growth hormone receptor and IGF-1 pathway. Furthermore, he discussed the role of alternate GH–IGF-1 pathways in those disorders caused by changes in the mitotic spindle that regulate the proper chromosome segregation process during cells division. An example was provided by Miller–McKusick–Malvaux syndrome, for which mutations in the CUL7 gene are responsible. CUL7 encodes for a component of the Cullin7 E3 ubiquitin ligase that contain Skp1, Fbx29 (also called Fbw8) and ROC1 proteins. It was shown that, due to the presence of CUL7 mutations, the impaired ubiquitination process may have a role in the pathogenesis of intrauterine growth retardation in humans.

MP Whyte (Shriners Hospital for Children, MO, USA) was presented the Henning Andersen Prize for best clinical abstract submitted to the ESPE 2010 Meeting, which was entitled ‘Hypophosphatasia: enzyme replacement therapy for affected children using bone-targeted, tissue nonspecific alkaline phosphatase’. Hypophosphatasia is a congenital metabolic disease caused by mutation(s) in the alkaline phosphatase gene. The authors studied the effect of a novel enzyme-replacement therapy using ENB-0040 in 13 children with hypophosphatasia. ENB-0040 is a bone-targeted, human recombinant tissue nonspecific alkaline phosphatase fusion protein that preserves skeletal mineralization in mice. They demonstrated that subcutaneous injections of ENB-0040 three-times a week led to the enhancement of skeletal mineralization process, significant improvements in muscle strength, radiological picture of bones, bone pain and bone biochemistry.

In turn, C Gaston-Massuet (University College London, London, UK) was awarded the Henning Andersen Prize for best basic abstract submitted to the ESPE 2010 Meeting. In the study entitled ‘Enhancement of the canonical Wnt pathway in Rathke‘s Pouch results in pituitary tumors reminiscent of human adamantinomatosus craniopharyngoma’, the authors focused on the fact that the Wnt/β-catenin signaling pathway is required for proper embryonic development, normal cell proliferation, differentiation and organ homeostasis in adult life. Overactivation of this pathway has been shown in various human cancers, including colon and skin cancers. After insertion of a gain-of-function β-catenin construct into a murine model, the researchers obtained offspring that suffered from hypopituitarism, extreme growth retardation and the development of tumors arising from Rathke‘s pouch. Those tumor cells were characterized by the presence of the same molecular marker as adamantinomatosus craniopharyngoma. This tumorogenic effect occurs only when this overactivation takes place in the undifferentiated, early Rathke‘s pouch progenitor cells of the anterior pituitary, but is absent in differentiated cells. The authors’ findings provide new insight into the role of Wnt pathway in the pituitary development and represent the first animal model for the study of human adamantinomatosus craniopharyngoma.

The Andrea Prader Prize is an annual Leadership Award and the most prestigious ESPE senior award to honor the overall contribution to the field of pediatric endocrinology that is awarded to a member of ESPE. This year it was presented to Z Hochberg (Technion – Israel Institute of Technology, Haifa, Israel), a basic and clinical researcher who is fully dedicated to the ESPE activities and initiatives. In his lecture he talked about the important role of various societies such as the ESPE in the education process of trainees from countries outside Europe and the USA. He also highlighted the need and important role of education and research opportunities taken from partnerships formed between pediatric endocrine societies around the globe.

Three ESPE activities were also mentioned during the ESPE 2010 Meeting, including winter and summer school, as well as ESPE science school (ESS). The last event was held for the first time in Varberg, Sweden in May 2010. ESS stands for a new and exciting ESPE initiative combined with the ‘New Inroads to Child Health’ conference. It serves as a great chance for young investigators in pediatric endocrinology to develop their research skills. The travel grants were aimed at PhD students in their final year, post-doctorates and research-active young pediatric endocrine investigators. A total of 20 travel grants were awarded to students from various countries, enabling them to interact with the most outstanding speakers, basic scientists and clinicians in the field.

The enormous advances of modern medical science was summarized in the 2010 Yearbook of Pediatric Endocrinology[1]. This book, coedited by several experts, presents the abstracts of very important published articles but also gives brief comments on their unusual significance to basic and clinical endocrinology.

Highlights

The 49th Annual ESPE Meeting held in Prague and chaired by J Lebl (Charles University in Prague, Prague, Czech Republic) was a very successful scientific and educational event covering the whole spectrum of pediatric endocrine problems, and we therefore highly recommend this meeting to all medical specialties involved in pediatric endocrine care.

This brief article was prepared selectively owing to many parallel sessions; however, the authors made every effort to make this report objective and focused on important clinical problems, new research findings and future perspectives in pediatric endocrinology.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.