FALL/WINTER 2014
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CONFERENCE OUTCOMES Advances in growth disorder treatment: Highlights from the conference in Istanbul, Turkey CONFERENCE OUTCOMES Latin America growth disorder issues: News from the symposium in Santiago, Chile
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HIGHLIGHTS ON EXCEMED ACTIVITIES IN ENDOCRINOLOGY AND METABOLISM YOUR EXCEMED Sharpening skills in endocrinology and metabolism practice through medical education UPCOMING IN EXCEMED ENDOCRINOLOGY AND METABOLISM EXCEMED CME events on the horizon
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Advances in diagnosis and treatment of growth disorders 10 MAY, ISTANBUL, TURKEY Pharmacogenomics, NGS and updates on growth disorder were discussed at length by delegates from Saudi Arabia, Germany, Turkey, Italy, Australia and South Korea at a one-day conference on the management of paediatric growth disorders.
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The educational goals of the Istanbul event were to: • Recognise the burden of paediatric growth disorders • Enhance knowledge of diagnosis and therapy, using approved guidelines • Improve the use of GH therapy in light of pharmacogenomics and long-term clinical evidence • Improve the use of GH therapy in patients with different clinical conditions and comorbidities • Improve treatment adherence in clinical practice Advances in growth disorder management have moved beyond research and into clinical settings, thereby offering new and improved options for treating and counselling those affected by all types of growth disorder.
CME EXCELLENCE Continuing medical education (CME) is our sole focus and our passion. We pour our energy and expertise into delivering the best for healthcare professionals, with patients as the ultimate beneficiaries. This is CME excellence. EXCEMED educational programmes in endocrinology and metabolism are designed to suit the needs of clinicians and scientists across the globe, working in primary, secondary and academic settings, who wish to remain up to date with all aspects of research and patient care.
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CONFERENCE OUTCOMES, 10 MAY, ISTANBUL, TURKEY
NGS/WES help identify genetic causes of short stature Professor Jan-Maarten Wit (Leiden University, the Netherlands) described NGS, particularly WES, as a powerful technique for solving diagnostic problems if a genetic cause of short stature is suspected
Novel forms of genetic analysis, including NGS, help to identify mutations associated with genetic causes of short stature Professor Wit described how NGS is of value in routine clinical assessment where a dominant, recessive or X-linked genetic cause of short stature is suspected. Currently, NGS often takes the form of WES: a technique that is rapidly and widely becoming available but is often underutilized in practice. To illustrate the clinical value of NGS, Professor Wit presented case examples in which WES identified specific variations in the genome, each associated with a different growth-related issue. FGFR3, linked to dominantproportionate short stature In cases of proportionate short stature, WES may reveal a heterozygous missense mutation in FGFR3 (c. 1584G>T, p.Met528Ile) in the tyrosine protein kinase domain, close to the hypochondroplasia mutation p.Asn540Lys.
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PAPSS2, skeletal dysplasia and SEMD A novel mutation of PAPSS2 is associated with skeletal dysplasia and SEMD. Serum DHEA and DHEA sulphate levels should be measured in children with SEMD, and in those with unexplained pubarche. If levels are elevated, PAPSS2 should be sequenced, to elucidate whether mutations are the cause of abnormal growth. PAPS is the universal sulphate donor; PAPSS2 mutations cause inactivations that impair DHEA sulphation and drive abnormal adrenal steroid levels and altered pubertal development (two common clinical findings observed in children with PAPSS2 mutations). IGSF1 and a novel X-linked syndrome Genetic alterations in IGSF1 - including premature truncations, in-frame mutations and whole-gene deletions are revealed by X-exome sequencing in families with known history of specific growth disorders: • Male subjects with mutations in IGSF1 have central hypothyroidism, macroorchidism and delayed puberty; some also have prolactin deficiency, short stature and/or obesity • Physiological manifestations are rarely seen in female subjects with IGSF-1 mutations: central hypothyroidism affects one-third of affected females. Family screening is warranted when genetic alterations in IGSF-1 are identified in an individual, given the heightened risk of cardiovascular events associated with hypothyroidism, added Professor Wit. NPR2 inactivation and short stature Homozygous inactivating NPR2 mutations are associated with acromesomelic dysplasia, Maroteaux type.
ENDOCRINOLOGY AND METABOLISM FALL-WINTER 2014
IN BRIEF Managing ISS (M Savage, UK ; J Chaplin, Sweden) • This is a controversial topic: different countries have their own approaches and GH therapy is not available globally • Some believe that GH therapy improves height by > 1 SDS (~3-7 cm), achieves predicted final height with minimal side-effects and reduces the psychological impact of ISS • Others believe that GH therapy is an expensive enhancement of appearance, with a relatively high percentage of non-responders, and limited psychological benefits • Assessing ISS holistically, including full psychological evaluation, helps to identify individuals at increased risk of psychological distress.
Transitional age and treatment (S Shalet, UK) • GH therapy in the transitional age (i.e. adolescence) is important in order to achieve a proper final height and a complete body composition (i.e. fat and muscle mass, and bone mineral density) • Poor GH treatment during and before adolescence can lead to fragility fractures and metabolic alterations, such as dyslipidemia or endothelial dysfunction, in later life Improving treatment adherence (S Norgren, Sweden) • Factors that influence adherence include daily painful injections, drug-related side-effects and lifestyle disruption, but a key reason is simply that people forget to give the injections • Tools to improve adherence at high risk include detailed education, family assistance, refill counting and electronic monitoring devices
Abbreviations are defined in the Glossary, page 6
CONFERENCE OUTCOMES, 10 MAY, ISTANBUL, TURKEY
PREDICT study brings pharmacogenomics to GH treatment The future management of GHD or TS may begin with pharmacogenomic analysis to predict therapeutic response, thereby influencing personalized GH treatment. Findings of the PREDICT1 study provide initial evidence of genetic markers and gene expression profiles that are associated with treatment response in GHD and TS.
Professor Chatelain outlined how PREDICT has evaluated 103 genes of the GR, IGF1 and insulin pathways, using SNP analysis in patients on GH therapy. Responses were analysed at 1 month for IGF1 generation, and at 1 year for height velocity. In GHD, genes associated with 1-year change in height following GH therapy were IGFBP3, GRB10, TGFA, INPPL1, TP53, CYP19A and SOS1 (Table 1). In TS, KRAS and LHX4 were associated with a significant increase in height at 1 year, following GH therapy. PREDICT data also indicate that 1 month’s GH therapy changes the expression of several genes involved in IGF pathway regulation.
Professor Pierre Chatelain (University of Claude Bernard, Lyon, France) explained how genetic analyses are helping to predict GH treatment response
Differences in gene expression for genes within the IGF and GR pathways were associated with poor IGF-1 generation; these markers showed little overlap between GHD and TS. IGF-1 is becoming well established as a genetically modulated and personalised marker of GH treatment response in GHD patients. Predicting individual IGF-1 response to GH treatment, using several genetic markers in one individual, may facilitate personalised treatment. Professor Chatelaine cautioned that independent analyses are needed in order to validate the PREDICT findings, however.
Table 1: Year 1 growth response (cm/y) following GH treatment in association with genetic markers identified in children with GHD (PREDICT study)
Gene SNP ID
Category
GRB10 C Allele rs933360 (non-marker) TT Genotype (marker) IRS1 C Allele (marker) rs22885869 GG Genotype (non-marker) SOS1 CC Genotype rs2888586 (non-marker) T Allele (marker) CYP19A1 GG Genotype rs10459592 (marker) T Allele (non-marker)
Median
Range
Mean
SD
Delta Means P-value (t-test) 95%CI LL 95%CI UL
40
N
7.8
4.0,12.0
8.0
1.7
-1.2
72
9.1
4.7,14.3
9.2
2.2
20 92
8.8 8.5
6.0,12.3 4.0,14.3
8.8 8.8
1.9 0.0 0.968 -1.0 2.1
33
7.9
4.0,12.0
7.9
1.8
79 29
8.8 10.0
5.1,14.3 4.0,14.3
9.1 9.8
2.1 2.5 1.4 0.002 0.5
83
8.0
4.7,13.0
8.4
1.8
-1.2
0.004
0.004
-1.9
-0.4
1.0
-2.0
-0.4
2.2
1
PREDICT: Large prospective study that is evaluating potential genetic and serological biomarkers that may predict GH treatment response in children with GHD or Turner’s syndrome (NCT00256126) GOT A COMMENT OR QUESTIONS? E-MAIL INFO@EXCEMED.ORG
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CONFERENCE OUTCOMES, 23-24 MAY 2014, SANTIAGO DE CHILE, CHILE
Meeting clinical and practical needs in growth disorder Dr Francesco De Luca (St Christopher’s Hospital for Children, Philadelphia, UAS) characterised undernutritionrelated growth failure and reviewed experimental evidence supporting a causative role for FGF21 in short stature
Chronic undernutrition remains a common environmental cause of faltering growth. Undernutrition starts a cascade of biological events that may even begin in utero. These events manifest in suboptimal GH levels and ultimately lead to short stature. Undernutrition continues to be a key cause of faltering growth which may lead to short stature in adult life. The highest rates of growth stunting are observed in Asia, Africa and Latin America and are of great socio-economic concern. The congress in paediatric growth disorder, held in Santiago de Chile, Chile, was therefore an important CME event attended by over 100 healthcare professionals, including paediatric endocrinologists and scientists. The learning objectives for this clinically focused event were to: • Improve diagnosis and therapy of growth disorders according to current guidelines and local needs • Recognize the role of pharmacogenomics in guiding GH therapy for growth disorders • Appraise the proper use of GH and other agents, including improving adherence 2
Hormonal mechanisms, undernutrition and stunting Growth stunting2 affects around 200 million children globally. Highest rates are observed in regions including Asia, Africa and Latin America, where undernutrition is of socio-environmental concern. Undernutrition impacts negatively on physical development even before birth. Dr De Luca described how a loss of up to 10 cm in mean height is observed in undernourished children, compared with well-nourished children of the same ethnic background. In addition, evidence for GH resistance (or insensitivity) in undernutrition-related growth failure, is expanding. Daily caloric intake, especially in terms of protein intake, is inversely correlated with height velocity and serum IGF1 levels, but not GH levels. Several animal experiments implicate FGF 21 in the development of short stature: FGF21 inhibits longitudinal bone growth. FGF21 expression increases in the liver and in the growth plate during periods of chronic undernutrition, thus leading to GH insensitivity. Increased FGF21 expression is also associated with IGF1 deficit.
IN BRIEF Factors influencing short stature in Latin America (I Bergadá, Argentina) • Growth disorders, especially ISS, are common in Latin America due to genetic heterogeneity and social inequalities across the continent • Indigenous communities are at particularly high risk, due to social inequality and undernutrition (reducing height in early life by up to 1 SDS from the mean) • Paediatricians should not delay in referring children with suspected growth disorder to specialist paediatric endocrinology services • Correct diagnosis and prompt initiation of therapy where indicated, can prevent short stature in adulthood Tailoring GH therapy for optimal growth (A Rogol, USA; P Chatelain, France) • Delaying epiphyseal maturation may facilitate attainment of target height, in children of short stature • In almost all cases where children receive GH, prepubertal height gain is of greatest importance • Adequate/timely ‘block’ of puberty, involving aromatase inhibitor or continuous GnRA therapy, delays the pubertal sprout and allows GH therapy to improve final height • Conversely, for conditions of short stature with delayed puberty (e.g. TS), administering sex hormones improves bone elongation/maturation and body composition Novel genetic deficits and tailored therapies (H Domené, Argentina) • A mutation of the RNPC3 gene has been linked to pituitary hypoplasia, low IGF1 and severe ISS • Defects involving genes in the GHIGFs axis and beyond are pathogenic causes of short stature • GH1 gene mutation may induce severe growth deficit by generating a mutant nonfunctioning protein • Statb5 protein mutations are associated with GH resistance: F646S is a STAT5B missense mutation linked to with low IGF1 levels, severe short stature and immune dysfunction • A deficit of ALS (transport protein of IGF1 found in ~13% of short-stature patients) has mutated variants that cause low IGF1 levels and severe growth disorder
Growth stunting is defined as length or height ≥ 2 SD below the mean
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ENDOCRINOLOGY AND METABOLISM FALL-WINTER 2014
Abbreviations are defined in the Glossary, page 6
CONFERENCE OUTCOMES, 23-24 MAY 2014, SANTIAGO DE CHILE, CHILE
Dr Margaret Boguszewski
Managing growth in infants with growth disorders
(Federal University of Paraná, Curitiba, Brazil) advocated healthy slower weight gain for IUGR/ SGA infants: rapid ‘catch up’ growth affects nutritional programming and causes central adiposity
When infants born with IUGR or SGA do not grow adequately in very early life, a well-managed regimen – involving GH therapy if appropriate – improves overall nutritional intake, body composition, lipid metabolism, and bone and muscle function. Incidences of type 2 diabetes or metabolic syndrome are not higher in young adults with IUGR or SGA history who undergo GH therapy. GH treatment in IUGR/SGA: more than growth effects IUGR and SGA are relatively common disorders that may lead to short stature if untreated. However, when managed by strategies that aim for rapid ‘catch-up’ growth, metabolic alterations and central adiposity may emerge. GH therapy, with a slower rate of growth, may be the preferred approach (Figure 1). GH-led strategies also confer beneficial effects on metabolism (i.e. carbohydrate, lipid and protein utilisation), and body composition (increased fat-free mass, reduced fat mass and higher bone mineral content), added Dr Boguszewski. Very rapid weight gain during the first three months of life is associated with ‘nutritional programming’. This may result in a higher percentage of body fat, central adiposity and metabolic problems in late childhood/adulthood. Conversely, 3 years’ GH treatment leads to a significant and steady improvement in height and weight in children born SGA (Figure 2).
Figure 1: IUGR and SGA are associated with health problems in adulthood that are less apparent following GH therapy than rapid weight gain
Figure 2: Effects of 3 years’ GH treatment in children born SGA. N= 156, children aged 2-4 years; N= 464, children aged 4-6 years
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GLOSSARY
YOUR EXCEMED
EXCEMED: sharpening skills through medical education EXCEMED – Excellence in Medical Education – is the new name of Serono Symposia International Foundation (SSIF). Our new name marks an exciting point in our evolution, but our focus on education in endocrinology and metabolism remains paramount. The Foundation has offered world-class education to thousands of healthcare professionals over the past four decades. During this time, over 1500 international scientific congresses have been organised, with more than 500 proceedings published in leading international journals. EXCEMED has pioneered online CME courses since 2000; the organisation oversees an expanding portfolio of e-learning activities including video lectures, CME-accredited online courses and symposia. These digital ventures reach over 12,500 people per month via the EXCEMED website or through e-newsletters.
CME, continuing medical education DHEA, dehydroepiandrosterone FGF, fibroblast growth factor GH, growth hormone GHD, growth hormone deficit GnRA, gonadotropin-releasing hormone analogue FGF, fibroblast growth factor GH, growth hormone GR, glucocordicoid receptor HRQoL, health-related quality of life IGF, insulin-like growth factor IUGR, intrauterine growth restriction ISS, idiopathic short stature NGS, next-generation sequencing SEMD, Spondylo-epi-metaphyseal dysplasia SGA, small for gestational age SNP, single nucleotide polymorphism TS, Turner syndrome WES, whole-exome sequencing
As a non-profit global organisation, EXCEMED is dedicated to improving the patient’s life through the provision of independent, high-impact CME to scientists, physicians, nurses, pharmacists and other healthcare professionals. Upcoming EXCEMED events of relevance to specialists in endocrinology and metabolism are summarised on the back page of this publication.
EXCEMED has an innovative educational programme in endocrinology and metabolism
EXCEMED is a non-profit organization dedicated to providing CME to healthcare professionals. This newsletter is intended for healthcare professionals and provides a brief summary of a selection of previous educational events. EXCEMED will make reasonable efforts to include accurate and current information, wherever possible, but makes no warranties or representations as to its accuracy or completeness. This information is provided “as is” without warranty of any kind, either express or implied, including but not limited to implied warranty of fitness for particular purpose. EXCEMED has implemented and maintains a Quality Management System which fulfils the requirements of the ISO 9001:2008 standard for the activity of design and provision of training events in the healthcare sector. © EXCEMED, 2014. All rights reserved. EXCEMED Excellence in Medical Education, Salita di S. Nicola da Tolentino, 1/b, 00187 Rome, Italy. © Copyright 2014 EXCEMED. All rights reserved.
Editorial development: Ray Ashton, Linda Edmondson, Michèle Piraux, Flaminia Masprone, Emma Wadland Design: katehouben.com Photos on pages 1, 3, 6, 8 and 10 courtesy of www.bigstockphoto.com
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ENDOCRINOLOGY AND METABOLISM FALL-WINTER 2014
Abbreviations are defined in the Glossary, page 6
UPCOMING IN EXCEMED ENDOCRINOLOGY AND METABOLISM
EXCEMED is offering two prestigious live educational events in the coming months. Please visit www.excemed.org to see the latest news on the endocrinology and metabolism educational programme
International School of Thyroid Ultrasonography PISA, ITALY 17-18 OCTOBER, 2014 SCIENTIFIC ORGANISERS P VITTI AND T RAGO, PISA, ITALY
Advances and challenges in the management of diabetes and thyroid disorders SAO PAULO, BRASIL 10-11 OCTOBER 2014 SCIENTIFIC ORGANISERS H GRAF, PARANĂ€, BRAZIL, M TAMBASCIA CAMPINAS, BRAZIL
AIM EXCEMED is collaborating with the Division of Endocrinology and Metabolism, Endocrine Unit # 1, Department of Clinical and Experimental Medicine, of the University of Pisa, Italy, in organizing an advanced course on thyroid ultrasonography focusing on new modalities for the diagnosis and treatment of thyroid nodules that will be exploring the practical aspects of US-guided diagnostic elastosonography and laser therapy in the management of thyroid nodules. The main objectives of this live educational course are to review the latest news in thyroid ultrasound diagnostic criteria and applications in presence of thyroid nodules and to teach tools for use in daily clinical practice regarding the execution of diagnostic elastosonography and laser treatment for benign nodules. KEY TOPICS diagnostic criteria for thyroid ultrasound, clinical applications of thyroid ultrasound; recognizing ultrasound patterns suggestive of malignancy, fine-needle aspiration biopsy of thyroid nodules; interventional approaches for benign thyroid nodules TARGET AUDIENCE endocrinologists, radiologists, internists, and any other healthcare professional involved in the diagnosis and treatment of thyroid nodules. FORMAT lectures, case illustrations, several opportunities for clinical practice on patients
AIM EXCEMED is organising a dedicated educational conference for health care professionals involved in the management of diabetes and thyroid disorders in Latin America; the content is relevant to others who work in regions at highest risk. This conference will review the most significant achievements of research in both fields, and will share best practice for the clinical management of these diseases. Type 2 diabetes is a growing problem in Latin America; its management is a challenge for the local healthcare systems and professionals, particularly because of the lack of standardised guidelines, limited medical services and limited public finance. Thyroid disorders are also very common in Latin America, mostly due to iodine deficiency but also to genetic factors, leading to nodular goitre and immune dysfunctions. Hypo- and hyperthyroidism, thyroid nodules and thyroid cancer present frequent challenges for local physicians and healthcare systems, requiring tailored medical intervention and standards of care using international guidelines. KEY TOPICS Guidelines on prediabetes, treating diabetes, pharmacological therapy, improving outcomes, iodine deficit, thyroid autoimmune diseases, gestational diabetes, thyroid disorders in pregnancy, complications/co morbidities of diabetes, managing thyroid nodules, thyroid cancers TARGET AUDIENCE Latin American diabetologists, endocrinologists, general practitioners and all healthcare professionals involved in managing diabetes or thyroid diseases. FORMAT lectures, clinical case studies, interactive workshops
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