Welcome to issue 33 DEAR FRIENDS AND COLLEAGUES, We are very enthusiastic about the forthcoming ESPE Meeting in September in Paris. The scientific programme is excellent, as always: full of new and hot topics with much ‘fuel for our brains’. We wish the President of the Congress, Jean-Claude Carel, and the Organising Committees every success. You can read more about the ESPE 2016 Meeting throughout this issue. In particular, Working Group sessions at ESPE Meetings are very popular (see page 7). Look at them in detail in the scientific programme at www.espe2016.org, and choose the one you want to attend. These gatherings bring together clinicians interested in the field, and create good opportunities for interaction and discussion of clinical matters. This year, the second terms of both Jan Lebl, Chair of ESPE’s Education and Training Committee, and Gary Butler, Chair of ESPE’s Clinical Practice Committee, are coming to an end during the ESPE Meeting. (There is an ongoing e-election for these two vacancies.) Both have put a great deal of effort into these very important areas of activity. On page 6, we are pleased to publish an interview with Jan, in which he reflects upon his achievements in education and training during his term of office. We are also delighted to include highlights from the plenary lectures that you can enjoy during ESPE 2016 (pages 3–4). We hope these previews whet your appetite! Last, but not least, my term as Editor of the ESPE Newsletter is coming to an end, along with those of two members of the Editorial Board, Indi and Gabriel. They have made an enormous contribution to the ongoing activities of the Newsletter and also to the creation of new ideas and initiatives. On page 7, we recall the development and progress of the Newsletter over recent years If you would like to step into our shoes, details of how to apply for the vacancies on the Editorial Board can be found below. As ever, please also remember that this is your Newsletter. If you would like to share any news, send it to [email protected] so that it can be included. We thank all our colleagues who have contributed to this issue of the Newsletter. I also thank the Editorial Board members, as always, for their hard work and enthusiasm.
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WE ARE LOOkING FORWARD to seeing many of you in Paris in a few weeks at ESPE 2016. You will find us at the ESPE Connect stand in the exhibition hall, where we will be showcasing ESPE membership and the many activities that we have to offer. As you will see from the information elsewhere in this issue, the event promises to be yet another great ESPE Meeting, with the usual mix of high quality research and opportunities to engage with your Society and your colleagues from around the world. A session dedicated to both ESPE’s Education and Training initiatives and ESPE’s Science activities will give you a chance to learn about the exciting opportunities that your Society has to offer. Come to room 252 AB during the lunch break on Monday 12 September to hear accounts from those involved in making these activities happen and those who have benefited from ESPE’s programmes. Video clips from last year’s session can be seen on the relevant pages of the ESPE website (www.eurospe.org). Either side of the ESPE Meeting are two of ESPE’s key schools. The Summer School is one of ESPE’s long-standing schools, and takes place on 6–9 September. Our relatively new Diabetes, Obesity and Metabolism (DOM) School will be held on 13–15 September. Both will benefit from the same fabulous venue: the beautiful Château de la Tour in Gouvieux. At the Annual Business Meeting in Paris, we will be announcing the results of our Council elections. We welcome any feedback you may have on the system. You can always get in touch via [email protected]. As always, keep looking out for news and deadlines in our monthly news alerts and on our website at www.eurospe.org.
THE ESPE SCIENCE SCHOOL and ESPE Advanced Seminar in Developmental Endocrinology are merging to form the ESPE Science Workshop. This will promote interaction on scientific issues between ESPE members, and encourage collaboration with basic researchers who are not ESPE members. The workshop will take place annually at a venue in Europe, and will be organised by a local Programme Organising Committee. Its theme can be any topic related to paediatric endocrinology. Applications are invited by 1 September 2016 to organise the 2017 event. For further information and the application form, see www.eurospe.org/education/ education_scienceworkshop.html. The ESPE Science Workshop is sponsored by an unrestricted grant from Pfizer.
If you are interested in diabetes, obesity and metabolism (DOM), why not apply to chair ESPE’s
DOM School Steering Committee?
The Chair has major responsibility for the ESPE DOM School programme. This involves emails
and preparation work, evaluation of submitted applications, and attendance at the School,
including an annual Steering Committee meeting.
The appointment is for a 3-year term and will be made by the ESPE Council. For more
information see www.eurospe.org/about/vacancies and www.eurospe.org/about/committees/
To apply, send an electronic copy of your CV and a covering letter to the ESPE Team at
[email protected] by 30 September 2016.
Environmental chemicals, thyroid hormone and human intelligence Saturday 10 September, 11:30–12:00 THYROID HORMONE IS THE ONLY HORMONE for which all babies are screened at birth. This is because it has been known for decades that the consequences of thyroid hormone insufficiency during postnatal development – cretinism – are severe and irreversible. However, the last 15 years have witnessed major, unexpected, insights into how thyroid hormone acts during prenatal brain development across vertebrates. For instance, even mild maternal hypothyroidism or hyperthyroidism during early pregnancy is associated with IQ reduction and modified brain structure in their children.1 Other recent discoveries include the tight control of tissue thyroid hormone levels by deiodinases and the existence of membrane thyroid hormone transporters (THTs). Mutations in THTs are associated with Allan-Herndon-Dudley syndrome, a severe form of intellectual and physical disability.2 In parallel with this increased understanding, we are witnessing an unprecedented increase in the incidence of autism spectrum disorders (ASD), often correlated with IQ loss. Although changes in diagnosis and awareness contribute to this increase, many authors consider environmental factors to be implicated.3 Four arguments support this hypothesis. First, numerous chemicals are found routinely in human amniotic fluid, including pesticides, plasticisers (e.g. phthalates, bisphenol A), nitrates, perchlorate, antimicrobials (such as triclosan), flame retardants, surfactants and mercury. Secondly, a number of categories of chemicals have been shown to be thyroid hormone disruptors. Thirdly, prenatal exposure to many chemicals is significantly associated with IQ loss and/or increased risk of ASD. Fourthly, chemical production has risen exponentially in the last few decades, continually increasing exposure. I shall present data on how we exploit the evolutionary conservation of thyroid signalling to use transgenic Xenopus as a screening tool for environmental chemicals affecting thyroid hormone signalling and brain development. I shall also consider the evidence that interference with thyroid hormone orchestration of human brain development could be implicated in the observed increase in neurodevelopmental disease, as well as in significant IQ loss at a population level, associated with enormous socio-economic costs.4 Barbara Demeneix, UMR 7221 CNRS/MNHN, Evolution des Régulations Endocriniennes, Paris, France References 1. korevaar et al. 2016 Lancet Diabetes & Endocrinology 4 35–43. 2. Lopez-Espindola et al. 2014 Journal of Clinical Endocrinology & Metabolism 99 E2799–E2804. 3. Demeneix 2014 Losing Our Minds: How Environmental Pollution Impairs Human Intelligence and Mental Health. Oxford: Oxford University Press. 4. Bellanger et al. 2015 Journal of Clinical Endocrinology & Metabolism jc20144323. Calcium-sensing receptor signalling in physiology and diseases Sunday 11 September, 11:30–12:00 THE ExTRACELLULAR CALCIUM (Cao 2+)-sensing receptor (CaSR), a G-protein coupled receptor, regulates Cao 2+ homeostasis by detecting alterations in Cao 2+ concentrations and activating G-protein mediated signalling cascades, which modulate parathyroid hormone (PTH) secretion and urinary calcium excretion. Much has been learnt about the role of the CaSR in calcium homeostasis by studying human disorders. Thus, CaSR mutations resulting in loss of function lead to familial hypocalciuric hypercalcemia (FHH), a life-long disorder associated with mild-to moderate elevations of serum calcium concentrations, normal or elevated PTH concentrations, and inappropriately low urinary calcium excretion. CaSR mutations are detected in ~65% of FHH patients, referred to as FHH type 1 (FHH1), and genetic studies in other FHH kindreds have revealed genetic heterogeneity and defined two additional types: FHH2 and FHH3. FHH2 is due to mutations of G-protein subunit α11 (Gα11), encoded by GNA11, and in vitro expression of FHH2-associated GNA11 mutations was found to diminish the sensitivity of CaSR-expressing cells to Cao 2+, consistent with a loss of function. FHH3 is due to loss-of-function mutations affecting adaptor protein-2 sigma subunit (AP2σ), encoded by AP2S1. AP2, a heterotetrameric complex, is involved in clathrin-mediated endocytosis. AP2σ mutations, which all affect the Arg15 residue that interacts with the dileucine motif of cargo proteins and comprise Arg15Cys, Arg15His and Arg15Leu, result in increased CaSR cell surface expression, probably due to decreased CaSR internalisation. Such AP2σ mutations are found in >20% of FHH patients who do not have CaSR or Gα11 mutations. These studies have provided new insights into CaSR signalling and trafficking, and advanced therapeutic options for disorders of calcium metabolism. Rajesh V Thakker, Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford, UK
Recent advances in the genetics of adrenal hyperfunction and tumours Saturday 10 September, 12:15–12:45 A VARIETY OF UNILATERAL adrenocortical tumours and bilateral nodular adrenal hyperplasia can be responsible for different types and levels of steroid excess. In the past, progress in understanding the molecular genetics of these diseases resulted from studying familial neoplasia syndromes, like Carney complex, or Li-Fraumeni or Beckwith-Wiedemann syndrome, in which adrenocortical tumours can be observed. More recently, genomics has led to spectacular and fast progress in this field. Exome sequencing identified somatic activating mutations of the catalytic subunit of protein kinase A (PRKACA) in cortisol-secreting adenomas responsible for overt Cushing’s. Combining pan-genomic single nucleotide polymorphism analysis and whole genome sequencing led to the identification of inactivating germline mutations of a novel tumour suppressor gene, ARMC5, in primary bilateral macronodular adrenal hyperplasia. The identification of ARMC5 as a gene frequently altered in primary bilateral macronodular adrenal hyperplasia revealed the hereditary nature of this adrenal cause of cortisol excess. The use of combined genomics in adrenocortical cancer revealed alterations of key driver genes such as CTNNB1, TP53, CDKN2A, DAXX, TERT, MEN1, RB1… and also a new tumour suppressor gene, ZNRF3, likely to control the Wnt/β-catenin pathway. Clearly the knowledge gained from genomics studies leads to a new vision of adrenocortical tumours and nodular hyperplasia classification based on molecular analysis. It also points to the involvement of two signalling pathways (cAMP and Wnt/β-catenin) that are important for adrenal cortex development and steroid synthesis. Interestingly, functional studies of the identified molecular alterations of these signalling pathways provides new perspectives to help understand these signalling cascades and to develop new drugs. These investigations, as well as development of mice models, also give new insights into adrenal development and the physiology and pathophysiology of steroid synthesis. This clearly shows that, depending on the type of molecular alteration, the balance between cell differentiation and proliferation affects steroid synthesis dysregulation, resulting in various disease phenotypes. Jérôme Bertherat, Service d’Endocrinologie, Hôpital Cochin, Paris, France Genetics of common and uncommon obesity Monday 12 September, 11:30–12:00 CURRENTLY, MORE PEOPLE ON EARTH are obese than are malnourished. The prevalence of obesity has dramatically increased worldwide, especially in children. In particular, the incidence of new severely obese children has increased in most populations. Although the environment is largely responsible for this ‘epidemic’ at society levels, genetics provides a good explanation for the difference in weight between individuals, in particular when young. The heritability of obesity is about 70% both in children and adults. About 5% of severely obese patients in Europe have a monogenic form of obesity, due to a defect in the control of appetite. Most DNA defects are point mutations, altering a protein function, but large chromosome deletions have also been found to cause obesity. One of them, on chromosome 16, is responsible for failure to thrive, and the opposite abnormality, with duplication of DNA, causes extreme leanness. However, in some populations at high levels of consanguinity, the proportion of elucidated monogenic forms of obesity reaches 30%. Next generation sequencing of the human genome now allows cost efficient and quick detection of these monogenic forms of obesity, and opens avenues for the identification of novel pathways controlling energy balance. The presence of monogenic obesity may have an impact on the outcomes of obesity surgery and thus should be detected. For common obesity, genome-wide association studies have identified more than 100 DNA variants increasing the risk of obesity in adults and in children. Mechanisms involved include appetite regulation, food intake behaviour, brain function, nutrient digestion and metabolism, but many of these genes don’t have known function. Epigenetic mechanisms may also contribute to obesity and to its complications. Philippe Froguel, Department of Genomics of Common Disease, Hammersmith Hospital, Imperial College Faculty of Medicine, London, UK
Bringing you recent highlights from the world of research
APPLIED FOR AN ESPE CLINICAL FELLOWSHIP in 2015–2016, with the aim of improving my clinical skills, widening my horizons and learning about the latest developments in paediatric endocrinology, in order to serve my patients better. I consider myself extremely fortunate to have been selected to undertake it at the Royal Manchester Children’s Hospital (RMCH), Manchester, Uk, under the expert supervision of Professor Leena Patel. She has helped me learn and assimilate as much as I could during my 3 months. The variety of cases that I got to see during my stay was phenomenal, from the rarest of the genetic causes of short stature to the rarest disorders of bone and calcium metabolism – I saw them all. A special mention must be made regarding the spectrum of RASopathies and late endocrine effects of cancer treatment, something I had only read about in books till now. As RMCH is a referral centre for congenital hyperinsulinism (part of the Northern Congenital Hyperinsulinism Service, or NORCHI), I saw plenty of cases being managed medically by conventional as well as more recent drugs, such as sirolimus and lanreotide. The NORCHI clinics in which the dedicated team followed up all the cases were also fabulous. Other than this, the video conferencing HPAT (hypothalamic pituitary axis tumours) discussions with other centres in Europe were very impressive. The multidisciplinary teamwork with radiology, gastroenterology, nephrology and genetics is really commendable. I was also involved in presenting the most complex cases to the team every week, and each of 10 September, 16:15–17:15 Adrenals Evangelia Charmandari (Greece) Evidence-based medicine in paediatric endocrinology Chris Kelnar (UK) Global health for the paediatric endocrinologist Jean-Pierre Chanoine (Canada) Type 2 diabetes, metabolic syndrome and lipids Orit Hamiel (Israel) Type 1 diabetes Wieland Kiess (Germany) 11 September, 09:15–10:15 Thyroid Gabor Szinnai (Switzerland) Oncology and chronic disease Carla Bizzarri (Italy) Reproductive endocrinology Olle Söder (Sweden) Bone, growth plate and mineral metabolism Outi Mäkitie (Finland) Editor’s choice Ken Ong (UK) 12 September, 08:00–09:00 Pituitary and neuroendocrinology Nicolas De Roux (France) Growth and growth factors Stefano Cianfarani (Italy) Antenatal and neonatal endocrinology Khalid Hussain (UK) Obesity and weight regulation Martin Wabitsch (Germany) The year in science and medicine Ze'ev Hochberg (Israel) M
ESPE is now more than 50 years old. Your Society has been uniting paediatric endocrinologists ever since its formation,
aiding communication and education and improving patient care. In this article, we look back at the Society's formative
1WHEN I TOOk OVER AS CHAIR of the ESPE Education and Training Committee in 2010, I could not fully appreciate the extent of the work ahead. It was more than I expected – but it was a truly rewarding mission. Now, after 6 years serving the Committee, I honestly feel that it might have been the biggest challenge of my professional life. I offer great thanks to everyone we worked with! I met new friends from around the globe, learned much from fellows, teachers and lecturers from different continents and, finally, understood that sharing knowledge is the ultimate achievement of a medical life. Nothing new in fact, as Hippocrates had the same thought! Besides the previously well-established teaching courses and fellowships, ESPE has initiated several new teaching projects in the past 6 years, to strengthen training opportunities in paediatric endocrinology in different parts of the world. Thanks to the enthusiasm of a francophone group of academic tutors chaired by Juliane Léger (Paris, France), the ESPE Maghreb School (supported by Pfizer) began for French-speaking North African countries, which substantially increased numbers of practising specialists in Morocco, Algeria and Tunisia. Five years of training has changed the scene completely, regarding the level of patient care, local medical activities and international research collaboration. The ESPE Caucasus & Central Asia School (supported by Ferring), which started in 2014, is a bilingual teaching course in English and Russian targeted at countries where the first foreign language is Russian. Originally devised by Malcolm Donaldson (Glasgow, Uk), it was brought to life by Rasa Verkauskiene (kaunas, Lithuania). Two previous courses in Almaty, kazakhstan, and Tashkent, Uzbekistan, will be followed by a third one in Baku, Azerbaijan, on 18–23 October this year. The local organisers and all fellows generate a warm and rewarding atmosphere that makes teaching in two languages on two screens in parallel much easier. Offering a unique opportunity to share clinical experience and knowledge between Arabic and European paediatric endocrinologists, the joint ASPED-ESPE School (with the Arab Society for Paediatric Endocrinology and Diabetes) was initiated by Asma Deeb (Abu Dhabi, United Arab Emirates). It is generously supported by Novo Nordisk Gulf. Due to various genetic backgrounds and different prevalence of consanguinity, the diagnostic spectrum of patients differs slightly between Arabic and European paediatric endocrine clinics, which makes the collaboration ever more challenging. The ESPE Diabetes, Obesity and Metabolism School covers extensive topics emerging all over the world. Attracting fellows from different continents, the teaching course, chaired by Moshe Phillip (Tel Aviv, Israel), covers novel aspects of genetics, pathophysiology and management of diabetes and obesity in a culturally sensitive way. It includes findings and best diagnostic and treatment solutions for countries with a range of socio-economic levels. Teaching collaboration with our colleagues in sub-Saharan Africa includes the Paediatric Endocrinology Training Centres for Africa in Nairobi, kenya, and Lagos, Nigeria. The ESPE Co-ordinator is currently Ieuan Hughes (Cambridge, Uk). There is also regular participation of ESPE delegates at annual meetings of the African Society for Paediatric and Adolescent Endocrinology (ASPAE). It was a great opportunity to take part and lecture in Durban (South Africa) in 2014, in Gaborone (Botswana) in 2015 and in khartoum (Sudan) earlier this year, and to see paediatric endocrinology in Africa growing stronger, and becoming ready to deliver care and medications to all children in need. Last but not least is ESPE’s continuing collaboration with our friends and colleagues in China and in India, as well as working and teaching together with ISPAD (the International Society for Pediatric and Adolescent Diabetes), APPES (the Asia Pacific Paediatric Endocrine Society) and other international groups. This makes the contribution of ESPE’s education and training activities truly global. Consider becoming personally involved in ESPE education and training. Start as a fellow, become a teacher, and take on one of the projects as a future project leader – that may be the way to make your mark in ESPE! Jan Lebl Chair, Education & Training Committee
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