Issue 44 – Summer 2019
Issue 44 - Summer 2019
Bringing The Latest In Paediatric Endocrinology To You
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Editorial
Welcome
Thanks to our excellent speakers, we are fortunate in this issue of ESPE News to have
insights into several of the talks you will be able to enjoy at ESPE 2021 Online. On page 6, Ali Abbara and Waljit Dhillo review our
understanding of kisspeptin’s role in puberty, with exciting potential developments in its therapeutic and diagnostic use. Meanwhile, on page 7, Peter Kühnen examines the melanocortin
4 receptor (MC4R) agonist setmelanotide as a treatment option in rare obesity syndromes. He explains the capacity of MC4R agonists to activate
different downstream signalling cascades (‘biased signalling’) and therefore elicit a range of effects. Supporting transgender/gender diverse youth
remains a complex and topical area of healthcare. Stephen Rosenthal discusses the associated issues, which he will address in his forthcoming presentation (page 8).
You can find out more about ESPE 2021
Online at www.eurospe.org/espe2021online.
As always, your contributions will form a central part of the meeting, so please make sure to submit your abstracts by 10 May 2021.
On page 4, we are extremely pleased to have contributions from colleagues in India about their lives in the time of COVID. Researchers
Anuradha Khadilkar and Vandana Jain reflect on the pandemic’s impact on their work with patients and other aspects of their research and daily
lives.The rest of the issue is bursting with the opportunities and support available to you from
ESPE. These extend from grants and committee vacancies to the prospect of future events such as ESPE Schools and the postponed ESPE Science
Symposium. Read on to learn more!We thank all this issue’s contributors for writing for us at such a busy and stressful time.
We wish them, you, and all your families and friends, health and peace in the coming months.
Sarah Ehtisham
Editor, ESPE News
Sarah.Ehtisham@mediclinic.a
News
Intro
Follow ESPE
online…
Keep an eye on
the latest ESPE news
and activities at
www.eurospe.org
You can also follow
ESPE on Facebook
and Twitter/EuroSPE
News
Clinical Fellowship
The Clinical Fellowship funds trainee paediatric endocrinologists to develop skills and knowledge in patient care, clinical management and clinical research by undertaking training in a specialised European clinical centre. Find out more at www.eurospe.org/grants-awards/grants/clinical fellowship and apply by 31 May 2019. “I was able to visit Sheffield in the UK and learn from well-known experts, not only in paediatric endocrinology, but also in genetics, gynaecology, neurosurgery and urology. I learned the importance of teamwork and its benefits for decision-making and improving patient care, and made valuable contacts with whom I will continue to exchange knowledge.” Huda Elhajburrani, Libya
News
ESPE Council elections
An e-vote this summer will enable ESPE members to elect the next Chairs of the: • Programme Organising Committee • Corporate Liaison Board • Education & Training Committee • Clinical Practice Committee. Details will follow by email. Please check we have your current email address by logging into the members’ area at www.eurospe.org
News
Could you host ESPE’s Science Symposium?
Would you like to plan and deliver a 1.5-day symposium on an area of paediatric endocrinology, with a budget of up to €30 000? We are welcoming applications from potential local organising committees for the 2020 ESPE Science Symposium. If you or your collaborative group would like to showcase the latest scientific knowledge, host topical discussions and provide networking opportunities for scientists and clinicians, please apply by 17 June. You can find guidelines, an application form and details of the successful inaugural 2018 Symposium at www.eurospe.org/education/espe science-symposium. The topic of your meeting should be attractive to researchers in basic or translational research, as well as ESPE members developing experimental and clinical research within and beyond paediatric endocrinology. We look forward to receiving your applications! Deadline 17 June 2019
News
Annual Review 2018
You can find the ESPE Annual Review for 2018 at www.eurospe. org/about/annual-review (you will also receive a copy by email). It gives a round-up of the Society’s activities from last year and celebrates all that ESPE continues to achieve − thanks to its members. With regret It was with great sadness that we heard of the recent passing of two ESPE members: Dr Birgit Köhler (Germany) and Dr Maria Kalina (Poland). We send our condolences to their families, friends, colleagues and patients. You can read their obituaries at www.eurospe.org/news
News
ESPE e-Learning
DSD in e-Learning Under ‘General Content’/Disorders of Sex Development: • 14 chapters concerning the initial endocrine approach, differential diagnosis, sex assignment and management of DSD, as well as psychological, social and cultural factors • 7 case studies Under ‘Resource Limited Countries’/Disorders of Sex Development: • the approach is divided into primary, secondary and tertiary care • 3 case studies
YNew items Under ‘General Content’/Calcium and Bone: • a case of a 9-month-old boy with hypercalcaemia (see image, right) Under ‘Resource Limited Countries’, new cases in: • Diabetes ISPAD Guidelines: Isha, a 2-year-old girl • Puberty: Amna, a 6-year-old girl with Down syndrome • Sodium and Water: Julie, a 10-year-old girl • Thyroid: a 13-year-old girl with weight loss
Hot topics
Intro
Bringing you recent highlights from the world of research
Hot topics
Is muscular fitness associated
with future health?
Muscular fitness is a valuable indicator for monitoring child and adolescent health. Despite this, recent evidence shows a decline in muscular fitness in school-age youth. To support the development of health-promoting strategies, it is important to monitor fitness levels in children and to quantify associations with health parameters later in life. García-Hermoso et al. performed a meta-analysis of articles that examined healthy children aged 3–18 years with muscular fitness assessed at baseline and a follow-up period of ≥1 year. They included 30 studies and found significant correlations with moderate−large (P < 0.05) effect sizes between muscular fitness at baseline and parameters for obesity (body mass index, skinfold thickness), cardio-metabolic health (homeostasis model assessment estimated insulin resistance, triglycerides, cardiovascular disease risk score) and bone mineral density at follow-up. They conclude that a negative association exists between muscular fitness in childhood/adolescence and adiposity and cardio-metabolic parameters in later life, together with a positive association for bone health.
Hot topics
Closing the loop on young
people with type 1 diabetes
This review summarises the developmental and physiological needs of young people with type 1 diabetes, and considers how hybrid closed-loop (HCL) systems could address these issues. Perhaps the most important feature of HCL systems is their ability to automatically regulate overnight insulin infusion rates, based on changes in sensor glucose values. Most studies of HCL technologies in young people show the superiority of closed-loop insulin delivery when compared with either conventional pump therapy or sensor-augmented pump therapy. The author considers features that could make the technology more attractive to these patients and their families as future-generation closed-loop systems are devised. Limited access to various system features may be desirable for youngsters. For paediatric patients, it is important to have alerts that are customisable, along with simplified strategies for meal announcement and managing glucose during exercise. Integration of HCL has the potential to minimise the burden of type 1 diabetes while improving glycaemic control and ultimately allowing paediatric patients to fulfill the primary goal of childhood: to be a kid
Hot topics
Colorectal cancer risk of a daily slice of bacon
In 2015, the World Health Organization classified processed meat as carcinogenic and red meat as probably carcinogenic to humans. The latest research by Bradbury et al. in a large contemporary prospective study of half a million men and women from the UK (including 2609 cases of incidental colorectal cancer) supports this statement. It indicates that consumption of red and processed meat at an average level of 76g/day (which meets the current UK Government’s recommendation of <90g/day) was associated with an increased risk of colorectal cancer. The risk was higher with consumption of processed meat than with red meat. Colorectal cancer increased by 19% with every 25g processed meat (equivalent to one rasher of bacon or one slice of ham), and by 18% with every 50g red meat (equivalent to one thick slice of roast beef or the edible portion of one lamb cutlet), that people ate per day.
Hot topics
Rotavirus vaccination and
type 1 diabetes
Rotavirus infection has been reported to be a risk factor for development of type 1 diabetes in children. Perrett et al. undertook an observational study in Australia, where children with newly diagnosed type 1 diabetes are registered with the National Diabetes Services Scheme. Using publicly available data, they examined the incidence of newly diagnosed type 1 diabetes in children between 0 and 14 years of age, in a period extending 8 years before and 8 years after oral rotavirus vaccination was introduced in 2007. Estimated national coverage for the vaccine was 84%. In children aged 0−4 years, the incidence decreased by 14% after introduction of the vaccine. There was no evidence of change over time in the pre-intervention and postintervention patterns of incidence. In children aged 5−9 years and 10−14 years, there was no change in the number of incident cases or temporal differences during the study period (2000−2015). Studies are ongoing to explore this association further.
Feature
Features
Caring for individuals
with DSD
The 2005 Chicago Consensus Meeting laid the foundation for a revised classification and model of care for the various conditions termed ‘differences of sex development’ (DSD). Since then, societal changes have placed further emphasis on children’s rights and autonomy, and on the demedicalisation of naturally occurring developmental variations. This evolution has to be reconciled now with the need for medical and psychosocial support experienced by many individuals and families. To this end, the EU funded COST (Co-operation for Science and Technology) Action ‘DSDnet, a systematic elucidation of DSD’, co-ordinated by Olaf Hiort, convened from 2013 to 2018. This network included experts and scientists from over 30 countries in Europe and internationally. A working group of this COST Action reflected on the requirements for a holistic and precise phenotypic description of individuals who have a DSD, and on the standardisation of care across ages and geographical regions. This resulted in the recent consensus document: www.nature.com/articles/s41574-018- 0010-8. This aims to tailor the cornerstones of contemporary DSD management to the principles of today’s society, while addressing the needs of those seeking holistic care, and to lay the foundations for multicentre, high quality, patient-centric research on outcomes of management. The main insights are highlighted below. What’s in a name? The terms ‘intersex’ and ‘disorders of sex development’ are problematic for many individuals, due to their association with gender identity and abnormality respectively. Terms such as ‘differences’ or ‘variations’ may circumvent these problems, but most people prefer a specific name for their condition, or an umbrella term avoiding the word ‘sex’. Optimising management Holistic management of DSD conditions is complex, and needs a multidisciplinary team (MDT). The individual conditions are very rare and require centralisation in a limited number of reference centres to guarantee sufficient expertise and optimal quality of care.
Transparency and transition Full transparency and comprehensive age-appropriate information from early childhood onwards have been related to positive adult outcomes. Many patients experience difficulties in finding specialised teams for adults who have a DSD condition or abandon medical care while transitioning to adult clinics. The consensus document discusses management of DSD across ages, with guidance for physicians who see these patients infrequently. Alternatives to early surgery There is increasing awareness that early genital surgery should be avoided whenever possible. However, it is clear that simple prohibition of such surgery is inadequate in addressing the needs of patients and families. Intensive counselling of families in how to raise resilient, self-confident children who have a genital difference is paramount, and may require extensive psychosocial support. Most healthcare systems do not foresee financial support for hospitals to organise this, or reimbursement of patients who receive these treatments. This requires the urgent attention of European and national health authorities. Assessing gender well-being Although the incidence of gender dysphoria is only marginally increased in individuals who have a DSD, many do not conform to a strict binary interpretation of gender and may adopt atypical gender roles. Thus, assessment of gender well-being and an individual’s opportunity to eventually have an atypical gender expression may be far more relevant than gender identity. From a societal point of view, a non-normative environment with regard to sex and gender may facilitate acceptance of the condition and improve well-being. Collaborative research The impact of recent management changes on psychosocial development and well-being is currently unknown. Systematic collection of standardised outcome data across centres in an international registry (e.g. the I-DSD registry; https://home.i-dsd.org) is paramount. By investing in future research to shed light on patient-centred long term outcome measures, we will improve the quality of care. This will also enhance discussions around integration of different gender expressions into our societies
Features
Human sex reversal
linked to enhancers
upstream of SOX9
Recent research by a team led by Andrew Sinclair
provides important insights into the genetics
underlying sex reversal
Gonadal sex differentiation in the embryo begins with the development of the bipotential gonads into testes or ovaries. Testis determination is initiated by the Y-linked SRY gene. SRY upregulates the gene encoding the transcription factor SOX9, which is necessary and sufficient for testis development. SOX9 tissue-specific expression is influenced by long-range regulatory elements within 2Mb upstream of the SOX9 transcriptional start site. While studies have identified enhancers regulating Sry-mediated Sox9 expression in mice, the human testis-specific enhancers remained to be fully elucidated. Redefining the landscape 46,XX and 46,XY patients with disorders of sex development (DSD) had previously been identified with copy number variants which hinted at deletions or duplications within two putative SOX9 upstream regulatory regions, denoted XYSR and RevSex. In recent work, the upstream regulatory landscape of human SOX9 has now been redefined using bioinformatics and luciferase tiling approaches, to identify enhancers for SOX9 expression. From a cohort of 44 patients with DSD, two duplications were identified in the XYSR regulatory region upstream of SOX9 in two unrelated patients. Since these duplications overlapped with each other and the XYSR region, it was anticipated that a core gonadal enhancer for SOX9 could be found in this critical region. Within this region, DNaseI hypersensitivity data revealed strong regulatory potential in human embryonic testes, but not in ovaries. The identified region was cloned as overlapping fragments and tested in several cell lines by luciferase assay using testicular transcription factors known to induce SOX9 expression. The strongest regulatory response was observed with a 1514bp fragment that probably contained the core enhancer. This genomic region was named sex reversal enhancer-A (eSR-A). This fragment contains consensus binding sites for the testicular transcription factors SRY/SOX9 and steroidogenic factor 1 (SF1). Thus, eSR-A contained a critical SOX9 enhancer that, when deleted in mice, results in 46,XY sex reversal and, when duplicated, causes 46,XX (ovo)testicular DSD in humans. By analysing a duplication in a 46,XX ovotesticular DSD patient within the RevSex region, a second SOX9 enhancer was identified, which is thought to contribute to SOX9 autoregulation. This involved an unbiased screening approach, cloning 16 overlapping fragments of a previously narrowed region within RevSex, and testing each for enhancer activity. Two of the fragments showed a significant increase in enhancer activity in response to SF1 and SOX9. The two fragments overlapped in a region that contained a highly conserved SOX9-binding motif. This region was designated sex reversal enhancer-B (eSR-B), a human-specific SOX9 gonadal enhancer that, when disrupted, can cause sex reversal. To locate an SRY-responsive enhancer of SOX9 in humans, bioinformatics screening was used to look for conserved enhancer marks upstream of SOX9 in publicly available databases. A locus was identified which contained a DNaseI hypersensitive site in embryonic testis, a putative SRY-binding site and strong active enhancer marks, and which was highly conserved between mice and humans. Since this fragment responded to the transcription factors SRY+SF-1 and SOX9+SF-1, but not SOX9 alone, it is probably important for SRY initiation of SOX9 expression in the developing testis. It was designated alternate long-distance initiator (eALDI) of SOX9. Suggesting a model Each of the enhancers mentioned above has an essential, yet distinct, role in initiating and maintaining human SOX9 expression. A model is suggested where SRY and SF1, which are expressed early in human testis development, bind eALDI as the primary enhancer to initiate SOX9 expression in the embryonic male gonad. Subsequently, SOX9 alone, or in combination with SF-1, binds sites within eSR-A, eSR-B and eALDI, to synergistically amplify testicular SOX9 expression in humans.
Features
Surgical intervention
in DSD
Melissa Gardner and David E Sandberg examine the
controversy surrounding surgery in DSD, and look for
paths forward
Disorders of sex development (DSD) encompass varied diagnoses and phenotypes, ranging from few somatic differences to those raising significant clinical management questions. Surgical procedures are particularly associated with contentious debate between and within stakeholder communities. Controversy All stakeholders seek what is in the best interests of the affected individual – although differences lie in how to arrive at that outcome. Additional areas of agreement include the following. (a) Early surgery in DSD is largely elective. With limited exceptions, irreversible decisions could be postponed until patients can be involved in discussions and provide assent, without jeopardising physical health. (b) Surgical interventions do not address several driving factors: parental anxiety, shame and desire for secrecy.1 Parents may feel stigmatised and seek to act quickly to ‘normalise’ their child’s genital appearance before becoming fully informed about all options, risks and benefits.2 While the intent of surgical management of the genitals and gonads is to benefit patients physically and psychosocially, these goals have not always been achieved. Grounded in reports of surgical complications and dissatisfaction among some who experienced early genitoplasty, intersex advocacy and human rights organisations condemn early DSD-related surgery, and call for a moratorium on all ‘medically unnecessary’ childhood genital and gonadal surgery. As gaps exist in high quality evidence that could be used to inform decision making on both individual and healthcare policy levels, some stakeholders have pursued means outside research to address their concerns. These include courts of law, legislative bodies, ethicists and human rights organisations. Less-often considered are potential risks or comparative outcomes associated with surgery performed later in life. Fundamental differences in perspectives extend to words used by different stakeholder groups; DSD care is burdened by varied and, frequently, polarised terminology. Paths forward Current efforts to ban elective genital surgery while a patient is too young to provide informed consent leaves two possible paths forward: eliminating all elective procedures until adulthood versus continuing to leave decisions to parents, providers and patients (when mature enough to participate). The birth of a child with a DSD, and attendant uncertainty about the child’s gender and psychological and somatic sex development, is considered extraordinarily stressful for parents.3 Many decisions made during this early period have permanent and far-reaching consequences for the child. The lack of accessible, clear information was noted as one of the most frustrating aspects of parenting a child with a DSD.4,5 Together with factors identified as strongly influencing the desire for surgical interventions (i.e. parental anxiety, shame, stigma and a desire to ‘fix’ or ‘normalise’ children’s genital appearance and/or function), lack of knowledge needs to be resolved by the healthcare team, regardless of whether decisions about elective surgery are considered. Indeed, advocates calling for the moratorium have also called for a robust patient- and family-centred approach to care, in which psychological services are essential. The act of ending or continuing access to elective surgical procedures during childhood is not an end itself; rather, we must address what drives the desire for these procedures. Provided elective surgical procedures remain available, a shared decision-making process is recommended. Decision support tools are designed to help people make deliberate choices among options by: • explicitly describing treatment choices • providing quantitative risk and benefit estimates, when available • tailoring information to individual patients, and • providing a context in which patients and parents can consider treatment options in light of their own values. Development and effective application of formalised decision support tools in the clinical context is an area in which patient advocates can hopefully collaborate with healthcare providers, rather than choosing the blunt tools of governmental legislation and lawsuits to resolve complex medical and social issues
Feature
Psychosexuality and
prenatal androgens
Rafael Loch Batista, Marlene Inacio and Berenice Mendonca’s studies of 46,XY individuals with DSD have shed light on the role of prenatal androgens in psychosexuality
Human sexual development is a dynamic process, regulated by genes and facilitated by endocrine mediators. This development starts in the neonatal period, after the bipotential gonads differentiate into testes in the presence of male-determining genes. Usually, these gonads will produce androgens.1 In the brain, androgens are able to virilise androgen sensitive areas which will affect the development of a male psychosexuality. In the absence of androgens (but not in the presence of oestrogens), human psychosexuality is driven to a female pathway.2 Many factors may play a role in human psychosexuality: genes, sex steroids, culture. The specific contribution of each is hard to estimate.3 The effects of androgens on the external genitalia (at 6−8 weeks of gestation) do not happen at the same time as they occur in the brain (in the second half of gestation). Consequently, virilisation of the brain and external genitalia do not occur in parallel in humans.4,5 It has largely been demonstrated that prenatal androgen exposure favours a male gender role and gynaephilic (female-driven) sexual orientation, but the association of that exposure with gender identity is less uniform. Differences of sex development (DSD) in 46,XY individuals are characterised by variable degrees of undervirilisation, according to 46,XY DSD aetiology. Many factors can have an impact on their psychosexuality. However, there is a relative lack of data on psychosexual outcomes in these patients. Assessing androgen impact To analyse the effect of prenatal androgen exposure, we divided a cohort of 46,XY DSD patients (n=144) according to prenatal androgen exposure.6 The frequency of male gender role at childhood, gynaephilic sexual orientation and male gender identity increased in accordance with the degree of prenatal androgen exposure. Gender change from female to male was frequent (19%; n=27) and happened only in individuals with prenatal androgen exposure. It is reasonable to consider that the presence of atypical external genitalia could affect the psychosexuality of both boys and girls. However, it is a questionable concept. In conditions such as cloacal exstrophy, penis ablation and 5α-reductase type 2 deficiency, there are several reports of male gender identity, despite severe external genitalia undervirilisation. Accordingly, our results showed that the virilisation score of external genitalia did not influence the psychosexuality of 46,XY individuals with different 46,XY DSD aetiologies. Collectively, this evidence suggests that external genitalia undervirilisation does not compromise male psychosexuality. The remaining question is whether virilisation of external genitalia could influence female psychosexuality. To answer this, we compared 46,XY DSD women with and without atypical external genitalia. In these women, all psychosexual parameters analysed were similar, suggesting a limited effect of external genitalia appearance on the psychosexual development of girls as well. In conclusion Our data show that androgens drive human psychosexuality. Their presence favours the development of a male psychosexuality, whereas female psychosexuality results from their absence. The virilisation of a fetus is an orchestrated event, where virilised external genitalia do not necessarily match a virilised brain. With regard to this discrepancy, the brain is stronger: a male psychosexuality is more likely to develop in a fetus exposed to androgens, regardless of the external genitalia virilisation score. Studies of people with 46,XY DSD reinforce the concept that prenatal androgen exposure is related to all male psychosexual outcomes, including gender identity. As 46,XY DSD is a heterogeneous condition, the aetiological diagnosis allows estimation of prenatal androgen exposure, which is helpful for counselling, management and sex assignment.
Events
Events
ESPE 2019: Variety and Variation
in Paediatric Endocrinology
Enjoy it all at ESPE 2019 The Annual ESPE Meeting is a rare and valuable opportunity for basic scientists and clinicians to network and collaborate. Showcasing the latest developments in paediatric endocrinology, ESPE 2019 has an exciting mix of basic science, translational research and clinical care, with something of interest to you all. Seven plenary lectures will display the diversity we see in our discipline, delivered by internationally renowned speakers from around the world (see panel for details). At ESPE 2019 you’ll also discover: • Eleven symposia focusing on advances in research, treatment and clinical endocrinology • The return of ‘How do I…?’ – highly regarded sessions, where you can learn how the experts manage paediatric endocrine conditions (see panel for details) • Novel Advances sessions, exploring cutting edge research techniques and their applications • Special sessions covering Working Groups, Controversies, Meet the Expert, the Yearbook of Pediatric Endocrinology and much more
Events
Plenary lectures at
ESPE 2019
RANKL and RANK: bone and beyond Josef Penninger, Canada Light, body clocks and sleep: biology to new therapeutics Russell Foster, UK Glucocorticoid rhythms, stress response and the brain from neonates to adult Stafford Lightman, UK Development of novel therapies for obesity Matthias H Tschöp, Germany Nutrition and the hypothalamo pituitary-gonadal axis Manuel Tena-Sempere, Spain How to reduce waste and increase value in translational biomedical research Ulrich Dirnagl, Germany Pituitary gigantism − an update Albert Beckers, Belgium
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