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1. The Growth Hormone Deficiency (GHD) Reversal Trial: effect on final height of discontinuation versus continuation of growth hormone treatment in pubertal children with isolated GHD—a non-inferiority Randomised Controlled Trial (RCT)

Author

Elizabeth Brettell, Wolfgang Högler, Rebecca Woolley, Carole Cummins, Jonathan Mathers, Raymond Oppong, Laura Roy, Adam Khan, Charmaine Hunt, Mehul Dattani, and on behalf of the G. H. D. study group

Subjects
Isolated growth hormone deficiency, Growth hormone, Final height, Early puberty, Reversal, Endocrine, Medicine (General), R5-920
Abstract

Abstract Background Growth hormone deficiency (GHD) is the commonest endocrine cause of short stature and may occur in isolation (I-GHD) or combined with other pituitary hormone deficiencies. Around 500 children are diagnosed with GHD every year in the UK, of whom 75% have I-GHD. Growth hormone (GH) therapy improves growth in children with GHD, with the goal of achieving a normal final height (FH). GH therapy is given as daily injections until adult FH is reached. However, in many children with I-GHD their condition reverses, with a normal peak GH detected in 64–82% when re-tested at FH. Therefore, at some point between diagnosis and FH, I-GHD must have reversed, possibly due to increase in sex hormones during puberty. Despite increasing evidence for frequent I-GHD reversal, daily GH injections are traditionally continued until FH is achieved. Methods/design Evidence suggests that I-GHD children who re-test normal in early puberty reach a FH comparable to that of children without GHD. The GHD Reversal study will include 138 children from routine endocrine clinics in twelve UK and five Austrian centres with I-GHD (original peak GH

Published
2023
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2. Starting point for benchmarking outcomes and reporting of pituitary adenoma surgery within the European Reference Network on Rare Endocrine Conditions (Endo-ERN): results from a meta-analysis and survey study

Author

Amir H Zamanipoor Najafabadi, Merel van der Meulen, Ana Luisa Priego Zurita, S Faisal Ahmed, Wouter R van Furth, Evangelia Charmandari, Olaf Hiort, Alberto M Pereira, Mehul Dattani, Diana Vitali, Johan P de Graaf, and Nienke R Biermasz

Subjects
endo-ern, pituitary, surgery, registry, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Objective: The European Reference Network on Rare Endocrine Conditions (Endo-ERN) aims to organize high-quality healthcare throughout Europe, inc luding care for pituitary adenoma patients. As surgery is the mainstay of treatment, we aimed to describe the current surgical practice and published surgical outcomes of pi tuitary adenoma within Endo-ERN. Design and Methods: Systematic review and meta-analysis of studies reporting surgical outcomes of pituitary adenoma patients within Endo-ERN MTG6 pituitary reference centers between 2010 and 2019. A survey was completed by refere nce centers on their current surgical practice. Results: A total of 18 out of 43 (42%) reference centers located in 7 of the 20 (35%) MTG6- represented countries published 48 articles. Remission rates we re 50% (95% CI: 42–59) for patients with acromegaly, 68% (95% CI: 60–75) for Cushing’s disease, and 53% (95% CI: 39–66%) for prolactinoma. Gross total resection was achieved in 49% (95% CI: 37–61%) of patients and visual improvement in 78% (95% CI: 68–87). Mort ality, hemorrhage, and carotid injury occurred in less than 1% of patients. New-onset hypopituitarism occurred in 16% (95% CI: 11–23), transient diabetes insipidus in 12% (95 % CI: 6–21), permanent diabetes insipidus in 4% (95% CI: 3–6), syndrome of inappropria te secretion of antidiuretic hormone (SIADH) in 9% (95% CI: 5–14), severe epist axis in 2% (95% CI: 0–4), and cerebrospinal fluid leak in 4% (95% CI: 2–6). Thirty-five (81 %) centers completed the survey: 54% were operated endoscopically and 57% were together with an ENT surgeon. Conclusion: The results of this study could be used as a first benchmark for the outcomes of pituitary adenoma surgery within Endo-ERN. However, the hete rogeneity between studies in the reporting of outcomes hampers comparability and warrants outcome collection through registries.

Published
2022
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3. Inaccuracies in plasma oxytocin extraction and enzyme immunoassay techniques

Author

Hoong-Wei Gan, Clare Leeson, Helen Aitkenhead, and Mehul Dattani

Subjects
Oxytocin, Enzyme-linked immunosorbent assay, Reverse-phase chromatography, Solid phase extraction, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Psychology, BF1-990
Abstract

Numerous studies have reported extensive associations between plasma oxytocin (OXT) concentrations and various human physiological and neurobehavioral processes. Measurement of OXT is fraught with difficulty due to its low molecular weight and plasma concentrations, with no consensus as to the optimal conditions for pre-analytical sample extraction, standards for immunoassay validation or the ideal protease inhibitors to prevent OXT degradation. Previous attempts at determining the efficacy of various purification techniques such as solid phase extraction (SPE) or ultrafiltration have only utilized human plasma samples, making it difficult to dissect out whether the effect of interference comes from the extraction process itself or cross-reactivity with other proteins. By testing these on pure OXT solutions, we demonstrate poor recovery efficacy and reliability of reversed phase SPE (maximum 58.1%) and ultrafiltration (

Published
2023
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4. Effectiveness and Overall Safety of NutropinAq® for Growth Hormone Deficiency and Other Paediatric Growth Hormone Disorders: Completion of the International Cooperative Growth Study, NutropinAq® European Registry (iNCGS)

Author

Regis Coutant, Jordi Bosch Muñoz, Cristina Patricia Dumitrescu, Dirk Schnabel, Caroline Sert, Valerie Perrot, and Mehul Dattani

Subjects
NutropinAq® (somatropin), rhGH, recombinant human GH, growth hormone deficiency, paediatric GH disorders, safety, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

ObjectiveThe International Cooperative Growth Study, NutropinAq® European Registry (iNCGS) (NCT00455728) monitored long-term safety and effectiveness of recombinant human growth hormone (rhGH; NutropinAq® [somatropin]) in paediatric growth disorders.MethodsOpen-label, non-interventional, post-marketing surveillance study recruiting children with growth disorders. Endpoints included gain in height standard deviation score (SDS), adult height, and occurrence of adverse events (AEs).Results2792 patients were enrolled. 2082 patients (74.6%) had growth hormone deficiency (GHD), which was isolated idiopathic in 1825 patients (87.7%). Non-GHD diagnoses included Turner syndrome (TS) (n=199), chronic renal insufficiency (CRI) (n=10), other non-GHD (n=498), and missing data for three participants. Improvements from baseline height SDS occurred at all time points to Month 132, and in all subgroups by disease aetiology. At Month 12, mean (95% CI) change in height SDS by aetiology was: idiopathic GHD 0.63 (0.61;0.66), organic GHD 0.71 (0.62;0.80), TS 0.59 (0.53; 0.65), CRI 0.54 (-0.49;1.56), and other non-GHD 0.64 (0.59;0.69). Mean height ( ± SD) at the last visit among the 235 patients with adult or near-adult height recorded was 154.0 cm ( ± 8.0) for girls and 166.7 cm ( ± 8.0) for boys. The most frequent biological and clinical non-serious drug-related AEs were increased insulin-like growth factor concentrations (314 events) and injection site haematoma (99 events). Serious AEs related to rhGH according to investigators were reported (n=30); the most frequent were scoliosis (4 events), epiphysiolysis (3 events), and strabismus (2 events).ConclusionsThere was an improvement in mean height SDS in all aetiology subgroups after rhGH treatment. No new safety concerns were identified.

Published
2021
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5. Whole-genome sequencing of patients with rare diseases in a national health system.

Author

Ernest Turro, William J. Astle, Karyn Megy, Stefan Gräf, Daniel Greene, Olga Shamardina, Hana Lango Allen, Alba Sanchis-Juan, Mattia Frontini, Chantal Thys, Jonathan Stephens, Rutendo Mapeta, Oliver S. Burren, Kate Downes, Matthias Haimel, Salih Tuna, Sri V. V. Deevi, Timothy J. Aitman, David L. H. Bennett, Paul Calleja, Keren Carss, Mark J. Caulfield, Patrick F. Chinnery, Peter H. Dixon, Daniel P. Gale, Roger James, Ania Koziell, Michael A. Laffan, Adam P. Levine, Eamonn R. Maher, Hugh S. Markus, Joannella Morales, Nicholas W. Morrell, Andrew D. Mumford, Elizabeth Ormondroyd, Stuart Rankin, Augusto Rendon, Sylvia Richardson, Irene Roberts, Noemi B. A. Roy, Moin A. Saleem, Kenneth G. C. Smith, Hannah Stark, Rhea Y. Y. Tan, Andreas C. Themistocleous, Adrian J. Thrasher, Hugh Watkins, Andrew R. Webster, Martin R. Wilkins, Catherine Williamson, James Whitworth, Sean Humphray, David R. Bentley, Stephen Abbs, Lara Abulhoul, Julian Adlard, Munaza Ahmed, Hana Alachkar, David J. Allsup, Jeff Almeida-King, Philip Ancliff, Richard Antrobus, Ruth Armstrong, Gavin Arno, Sofie Ashford, Anthony Attwood, Paul Aurora, Christian Babbs, Chiara Bacchelli, Tamam Bakchoul, Siddharth Banka, Tadbir Bariana, Julian Barwell, Joana Batista, Helen E. Baxendale, Phil L. Beales, Agnieszka Bierzynska, Tina Biss, Maria A. K. Bitner-Glindzicz, Graeme C. M. Black, Marta Bleda, Iulia Blesneac, Detlef Bockenhauer, Harm Bogaard, Christian J. Bourne, Sara Boyce, John R. Bradley, Eugene Bragin, Gerome Breen, Paul Brennan, Carole Brewer, Matthew Brown, Andrew C. Browning, Michael J. Browning, Rachel J. Buchan, Matthew S. Buckland, Teofila Bueser, Carmen Bugarin Diz, John Burn, Siobhan O. Burns, Nigel Burrows, Carolyn Campbell, Gerald Carr-White, Ruth Casey, Jenny Chambers, John Chambers, Melanie M. Y. Chan, Calvin Cheah, Floria Cheng, Manali Chitre, Martin T. Christian, Colin Church, Jill Clayton-Smith, Maureen Cleary, Naomi Clements Brod, Gerry Coghlan, Elizabeth Colby, Trevor R. P. Cole, Janine Collins, Peter W. Collins, Camilla Colombo, Cecilia J. Compton, Robin Condliffe, Stuart A. Cook, H. Terence Cook, Nichola Cooper, Paul A. Corris, Abigail Furnell, Fiona Cunningham, Nicola S. Curry, Antony J. Cutler, Matthew J. Daniels, Mehul Dattani, Louise C. Daugherty, John Davis, Anthony De Soyza, Timothy Dent, Charu Deshpande, Eleanor F. Dewhurst, Sofia Douzgou, Anna M. Drazyk, Elizabeth Drewe, Daniel Duarte, Tina Dutt, J. David M. Edgar, Karen Edwards, William Egner, Melanie N. Ekani, Perry Elliott, Wendy N. Erber, Marie Erwood, Maria C. Estiu, Dafydd Gareth Evans, Gillian Evans, Tamara Everington, Mélanie Eyries, Hiva Fassihi, Remi Favier, Jack Findhammer, Debra Fletcher, Frances A. Flinter, R. Andres Floto, Tom Fowler, James Fox, Amy J. Frary, Courtney E. French, Kathleen Freson, Henning Gall, Vijeya Ganesan, Michael Gattens, Claire Geoghegan, Terence S. A. Gerighty, Ali G. Gharavi, Stefano Ghio, Hossein-Ardeschir Ghofrani, J. Simon R. Gibbs, Kate Gibson, Kimberly C. Gilmour, Barbara Girerd, Nicholas S. Gleadall, Sarah Goddard, David B. Goldstein, Keith Gomez, Pavels Gordins, David Gosal, Jodie Graham, Luigi Grassi, Lynn Greenhalgh, Andreas Greinacher, Paolo Gresele, Philip Griffiths, Sofia Grigoriadou, Russell J. Grocock, Detelina Grozeva, Mark Gurnell, Scott Hackett, Charaka Hadinnapola, William M. Hague, Rosie Hague, Matthew Hall, Helen L. Hanson, Eshika Haque, Kirsty Harkness, Andrew R. Harper, Claire L. Harris, Daniel Hart, Ahamad Hassan, Grant Hayman, Alex Henderson, Archana Herwadkar, Jonathan Hoffman, Simon Holden, Rita Horvath, Henry Houlden, Arjan C. Houweling, Luke S. G. E. Howard, Fengyuan Hu, Gavin Hudson, Joseph Hughes, Aarnoud P. Huissoon, Marc Humbert, Sarah Hunter, Matthew E. Hurles, Melita Irving, Louise Izatt, Sally A. Johnson, Stephen Jolles, Jennifer Jolley, Dragana Josifova, Neringa Jurkute, Tim Karten, Johannes Karten, Mary A. Kasanicki, Hanadi Kazkaz, Rashid Kazmi, Peter Kelleher, Anne M. Kelly, Wilf Kelsall, Carly Kempster, David G. Kiely, Nathalie Kingston, Robert Klima, Nils Koelling, Myrto Kostadima, Gabor Kovacs, Roman Kreuzhuber, Taco W. Kuijpers, Ajith Kumar, Dinakantha Kumararatne, Manju A. Kurian, Fiona Lalloo, Michele Lambert, Allan Lawrie, D. Mark Layton, Nick Lench, Claire Lentaigne, Tracy Lester, Rachel Linger, Hilary Longhurst, Lorena E. Lorenzo, Eleni Louka, Paul A. Lyons, Rajiv D. Machado, Robert V. MacKenzie Ross, Bella Madan, Jesmeen Maimaris, Samantha Malka, Sarah Mangles, Kevin J. Marchbank, Stephen Marks, Hanns-Ulrich Marschall, Andrew G. Marshall, Jennifer Martin, Mary Mathias, Emma Matthews, Heather Maxwell, Paul McAlinden, Mark I. McCarthy, Harriet McKinney, Aoife McMahon, Stuart Meacham, Adam J. Mead, Ignacio Medina Castello, Sarju G. Mehta, Michel Michaelides, Carolyn Millar, Shehla N. Mohammed, Shahin Moledina, David Montani, Anthony T. Moore, Monika Mozere, Keith W. Muir, Andrea H. Nemeth, William G. Newman, Michael Newnham, Sadia Noorani, Paquita Nurden, Jennifer O'Sullivan, Samya Obaji, Chris Odhams, Steven Okoli, Andrea Olschewski, Horst Olschewski, Kai Ren Ong, S. Helen Oram, Willem H. Ouwehand, Claire Palles, Sofia Papadia, Soo-Mi Park, David Parry 0003, Smita Patel, Joan Paterson, Andrew Peacock, Simon H. Pearce, John Peden, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, Romina Petersen, Clarissa Pilkington, Kenneth E. S. Poole, Radhika Prathalingam, Bethan Psaila, Angela Pyle, Richard Quinton, Shamima Rahman, Anupama Rao, F. Lucy Raymond, Paula J. Rayner-Matthews, Christine Rees, Tara Renton, Christopher J. Rhodes, Andrew S. C. Rice, Alex Richter, Leema Robert, Anthony Rogers, Sarah J. Rose, Robert Ross-Russell, Catherine Roughley, Deborah M. Ruddy, Omid Sadeghi-Alavijeh, Nilesh J. Samani, Crina Samarghitean, Ravishankar B. Sargur, Robert N. Sarkany, Simon Satchell, Sinisa Savic, John A. Sayer, Genevieve Sayer, Laura Scelsi, Andrew M. Schaefer, Sol Schulman, Richard Scott, Marie Scully, Claire Searle, Werner Seeger, Arjune Sen, W. A. Carrock Sewell, Denis Seyres, Neil Shah, Susan E. Shapiro, Adam C. Shaw, Patrick J. Short, Keith Sibson, Lucy Side, Ilenia Simeoni, Michael A. Simpson, Matthew C. Sims, Suthesh Sivapalaratnam, Damian Smedley, Katherine R. Smith, Katie Snape, Nicole Soranzo, Florent Soubrier, Laura Southgate, Olivera Spasic-Boskovic, Simon Staines, Emily Staples, Charles A. Steward, Kathleen E. Stirrups, Alex Stuckey, Jay Suntharalingam, Emilia M. Swietlik, Petros Syrris, R. Campbell Tait, Kate Talks, Katie Tate, John M. Taylor, Jenny C. Taylor, James E. Thaventhiran, Ellen Thomas, David Thomas 0004, Moira J. Thomas, Patrick Thomas, Kate Thomson, Glen Threadgold, Tobias Tilly, Marc Tischkowitz, Catherine Titterton, John A. Todd, Cheng-Hock Toh, Bas Tolhuis, Ian P. Tomlinson, Mark Toshner, Matthew Traylor, Carmen Treacy, Paul Treadaway, Richard Trembath, Wojciech Turek, Philip Twiss, Tom Vale, Chris Van Geet, Natalie van Zuydam, Maarten Vandekuilen, Anthony M. Vandersteen, Marta Vazquez-Lopez, Julie von Ziegenweidt, Anton Vonk-Noordegraaf, Annette Wagner, Quinten Waisfisz, Suellen M. Walker, Neil Walker, Klaudia Walter, James S. Ware, Christopher Watt, Lucy Wedderburn, Wei Wei, Steven B. Welch, Julie Wessels, Sarah K. Westbury, John-Paul Westwood, John Wharton, Deborah Whitehorn, Andrew O. M. Wilkie, Brian T. Wilson, Edwin K. S. Wong, Nicholas W. Wood, Yvette Wood, Christopher Geoffrey Woods, Emma R. Woodward, Stephen J. Wort, Austen Worth, Michael Wright, Katherine Yates, Patrick F. K. Yong, Timothy Young, Ping Yu, Patrick Yu-Wai-Man, and Eliska Zlamalova

Published
2020
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6. A homozygous <scp>Y443C</scp> variant in the <scp> RNPC3 </scp> is associated with severe syndromic congenital hypopituitarism and diffuse brain atrophy

Author

Diğdem Bezen, Orkide Kutlu, Stephane Mouilleron, Karine Rizzoti, Mehul Dattani, Tulay Guran, Gözde Yeşil, Bezen D., Kutlu O., Mouilleron S., Rizzoti K., Dattani M., Güran T., Yesil G., and Bezen D., Kutlu O., Mouilleron S., Rizzoti K., Dattani M., GÜRAN T., Yesil G.

Subjects
Internal Diseases, GENETİK VE KALITIM, Endocrinology, Diabetes and Metabolism, Endocrinology and Metabolic Diseases, Sağlık Bilimleri, Pediatrics, İç Hastalıkları, Clinical Medicine (MED), Endocrinology, DEVELOPMENTAL DISORDER, Klinik Tıp (MED), Pediatri, Perinatoloji ve Çocuk Sağlığı, GENETICS & HEREDITY, MUTATION, Genetics (clinical), Klinik Tıp, Moleküler Biyoloji, MINOR SPLICEOSOME, Temel Bilimler, RNU4ATAC, neurodegeneration, Life Sciences, Tıp, MOLECULAR BIOLOGY & GENETICS, ENDOKRİNOLOJİ VE METABOLİZMA, Medicine, PEDİATRİ, Natural Sciences, Medical Genetics, Endokrin ve Otonom Sistemler, ENDOCRINOLOGY & METABOLISM, Life Sciences (LIFE), Molecular Biology and Genetics, Endokrinoloji, Çocuk Sağlığı ve Hastalıkları, Child Health and Diseases, syndromic congenital hypopituitarism, Tıbbi Genetik, Yaşam Bilimleri, Health Sciences, Genetics, Genetik, Molecular Biology, Moleküler Biyoloji ve Genetik, Internal Medicine Sciences, Endocrine and Autonomic Systems, Dahili Tıp Bilimleri, CLINICAL MEDICINE, RNPC3, COMPONENT, Pediatri, Yaşam Bilimleri (LIFE), Pediatrics, Perinatology and Child Health, Endokrinoloji ve Metabolizma Hastalıkları, Genetik (klinik), neuropathy, Endokrinoloji, Diyabet ve Metabolizma, brain atrophy
Abstract

Biallelic RNPC3 variants have been reported in a few patients with growth hormone deficiency, either in isolation or in association with central hypothyroidism, congenital cataract, neuropathy, developmental delay/intellectual disability, hypogonadism, and pituitary hypoplasia. To describe a new patient with syndromic congenital hypopituitarism and diffuse brain atrophy due to RNPC3 mutations and to compare her clinical and molecular characteristics and pituitary functions with previously published patients. A 20-year-old female presented with severe growth, neuromotor, and developmental delay. Her weight, height, and head circumference were 5135 gr (-25.81 SDS), 68 cm (-16.17 SDS), and 34 cm (-17.03 SDS), respectively. She was prepubertal, and had dysmorphic facies, contractures, and spasticity in the extremities, and severe truncal hypotonia. There were no radiological signs of a skeletal dysplasia. The bone age was extremely delayed at 2 years. Investigation of pituitary function revealed growth hormone, prolactin, and thyroid-stimulating hormone deficiencies. Whole-exome sequencing revealed a novel homozygous missense (c.1328A > G; Y443C) variant in RNPC3. Cranial MRI revealed a hypoplastic anterior pituitary with diffuse cerebral and cerebellar atrophy. The Y443C variant in RNPC3 associated with syndromic congenital hypopituitarism and abnormal brain development. This report extends the RNPC3-related hypopituitarism phenotype with a severe neurodegenerative presentation.

Published
2022
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7. Tolvaptan and urea in paediatric hyponatraemia

Author

Faidra Veligratli, Demitra Alexandrou, Sarit Shah, Rakesh Amin, Mehul Dattani, Hoong-Wei Gan, Adeola Famuboni, Camilo Lopez Garcia, Richard Trompeter, and Detlef Bockenhauer

Abstract

Background: The syndrome of inappropriate antidiuretic hormone (SIADH) is usually treated with fluid restriction. This can be challenging in patients with obligate fluid intake for nutrition or medication. Pharmaceutical treatment with tolvaptan and urea is available but minimal paediatric data are available. We review the efficacy and safety of tolvaptan and urea in paediatric patients diagnosed with SIADH. Methods: Retrospective review of paediatric inpatients with clinical diagnosis of SIADH. Patients were identified from pharmacy records, based on tolvaptan and urea prescriptions. Relevant information was extracted from patient electronic records. The main outcome measures included: number of days to sodium normalisation, daily change in plasma sodium concentration and maximum increase of plasma sodium concentration in 24hrs . Reported side effects were also captured. Results: Tolvaptan use led to plasma sodium normalisation in 10/13 (77%) within six days (median 2.5 days, range [1,6]) with a median change of sodium concentration of 7 mmol/L (-1,14) within the first 24 hours of treatment. Three patients experienced a change in plasma sodium >10 mmol/l/day but had no apparent side effects. Urea use led to sodium normalisation in 5/6 (83%) patients. Median number of days to normalisation with urea was 2 (1,10) with a median change of plasma sodium concentration of 2 mmol/L (-1,6) within the first 24hours. All patients tolerated tolvaptan and/or urea without unexpected side effects. Conclusions: Tolvaptan and urea appear to be safe and effective when fluid restriction is challenging in paediatric SIADH.

Published
2023
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10. Starting point for benchmarking outcomes and reporting of pituitary adenoma surgery within the European Reference Network on Rare Endocrine Conditions (Endo-ERN)

Author

Amir H Zamanipoor Najafabadi, Merel van der Meulen, Ana Luisa Priego Zurita, S Faisal Ahmed, Wouter R van Furth, Evangelia Charmandari, Olaf Hiort, Alberto M Pereira, Mehul Dattani, Diana Vitali, Johan P de Graaf, Nienke R Biermasz, D Steenvoorden, I Bowring, MM van der Klauw, RA Vergeer, M Losa, P Mortini, W Drake, J Grieve, M Didi, C Mallucci, MG Shaikh, S Hassan, JOL Jorgensen, M Albarazi, S Zaharieva, A. Hadzhiyanev, M Tóth, L Sípos, D Unuane, J D'Haens, U Feldt-Rasmussen, L Poulsgaard, T Brue, H Dufour, J Bertherat, S Gaillard, N Karavitaki, S Ahmed, N Unger, I Kreitschmann-Andermahr, S Gaztambide, I Pomposo, H-W Gan, N Dorward, E Fliers, J Hoogmoed, C Scaroni, L Denaro, A Nordenström, M Olsson, B Zilaitiene, A Tamašauskas, L Persani, G Lasio, D Maiter, C Raftopoulos, V Volke, T Rätsep, P Matarazzo, P Peretta, T Deutschbein, J Perez, S Zucchini, D Mazzatenta, S Grottoli, F Zenga, F Devuyst, O De Witte, F Gatto, D Rossi, K Schilbach, W Rachinger, A Beckers, D Martin, M Al-Mrayat, N Mathad, SJCMM Neggers, AHG Dallenga, J Lebl, M Tichy, MM Reincke, AC van de Ven, E van Lindert, P Kotnik, R Bošnjak, B Biagetti, E Cordero, A Colao, P Cappabianca, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - SSS/IREC/EDIN - Pôle d'endocrinologie, diabète et nutrition, UCL - (SLuc) Service d'endocrinologie et de nutrition, UCL - (SLuc) Service de neurochirurgie, and Internal Medicine

Subjects
surgery, Endocrinology, SDG 3 - Good Health and Well-being, Endocrinology, Diabetes and Metabolism, Internal Medicine, Endo-ERN, registry, pituitary
Abstract

Objective The European Reference Network on Rare Endocrine Conditions (Endo-ERN) aims to organize high-quality healthcare throughout Europe, including care for pituitary adenoma patients. As surgery is the mainstay of treatment, we aimed to describe the current surgical practice and published surgical outcomes of pituitary adenoma within Endo-ERN. Design and Methods Systematic review and meta-analysis of studies reporting surgical outcomes of pituitary adenoma patients within Endo-ERN MTG6 pituitary reference centers between 2010 and 2019. A survey was completed by reference centers on their current surgical practice. Results A total of 18 out of 43 (42%) reference centers located in 7 of the 20 (35%) MTG6-represented countries published 48 articles. Remission rates were 50% (95% CI: 42–59) for patients with acromegaly, 68% (95% CI: 60–75) for Cushing’s disease, and 53% (95% CI: 39–66%) for prolactinoma. Gross total resection was achieved in 49% (95% CI: 37–61%) of patients and visual improvement in 78% (95% CI: 68–87). Mortality, hemorrhage, and carotid injury occurred in less than 1% of patients. New-onset hypopituitarism occurred in 16% (95% CI: 11–23), transient diabetes insipidus in 12% (95% CI: 6–21), permanent diabetes insipidus in 4% (95% CI: 3–6), syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in 9% (95% CI: 5–14), severe epistaxis in 2% (95% CI: 0–4), and cerebrospinal fluid leak in 4% (95% CI: 2–6). Thirty-five (81%) centers completed the survey: 54% were operated endoscopically and 57% were together with an ENT surgeon. Conclusion The results of this study could be used as a first benchmark for the outcomes of pituitary adenoma surgery within Endo-ERN. However, the heterogeneity between studies in the reporting of outcomes hampers comparability and warrants outcome collection through registries.

Published
2023

11. Genetic evaluation supports differential diagnosis in adolescent patients with delayed puberty

Author

Gary Butler, Mehul Dattani, Leo Dunkel, Helen L Storr, Kausik Banerjee, Tansit Saengkaew, Heena R Patel, Ruben H Willemsen, Michael McGuigan, and Sasha Howard

Subjects
Male, Delayed puberty, medicine.medical_specialty, Pediatrics, Adolescent, Genotype, Endocrinology, Diabetes and Metabolism, Context (language use), Genome-wide association study, Cohort Studies, Diagnosis, Differential, Endocrinology, Predictive Value of Tests, Hypogonadotropic hypogonadism, Internal medicine, Exome Sequencing, Humans, Medicine, Computer Simulation, Exome, Genetic Testing, Exome sequencing, Retrospective Studies, Genetic testing, Puberty, Delayed, medicine.diagnostic_test, business.industry, Hypogonadism, Computational Biology, Genetic Variation, Reproducibility of Results, Retrospective cohort study, General Medicine, medicine.disease, body regions, Clinical Study, Female, Differential diagnosis, medicine.symptom, business, Genome-Wide Association Study
Abstract

Context Pubertal delay can be the clinical presentation of both idiopathic hypogonadotropic hypogonadism (IHH) and self-limited delayed puberty (SLDP). Distinction between these conditions is a common but important diagnostic challenge in adolescents. Objective To assess whether gene panel testing can assist with clinical differential diagnosis and to allow accurate and timely management of delayed puberty patients. Design Retrospective study. Methods Patients presenting with delayed puberty to UK Paediatric services, followed up to final diagnosis, were included. Whole-exome sequencing was analysed using a virtual panel of genes previously reported to cause either IHH or SLDP to identify rarely predicted deleterious variants. Deleterious variants were verified by in silico prediction tools. The correlation between clinical and genotype diagnosis was analysed. Results Forty-six patients were included, 54% with a final clinical diagnosis of SLDP and 46% with IHH. Red flags signs of IHH were present in only three patients. Fifteen predicted deleterious variants in 12 genes were identified in 33% of the cohort, with most inherited in a heterozygous manner. A fair correlation between final clinical diagnosis and genotypic diagnosis was found. Panel testing was able to confirm a diagnosis of IHH in patients with pubertal delay. Genetic analysis identified three patients with IHH that had been previously diagnosed as SLDP. Conclusion This study supports the use of targeted exome sequencing in the clinical setting to aid the differential diagnosis between IHH and SLDP in adolescents presenting with pubertal delay. Genetic evaluation thus facilitates earlier and more precise diagnosis, allowing clinicians to direct treatment appropriately.

Published
2021
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17. Visual impairment, severe visual impairment, and blindness in children in Britain (BCVIS2): a national observational study

Author

Lucinda J Teoh, Ameenat Lola Solebo, Jugnoo S Rahi, Joe Abbott, Wajda Abdullah, Gill Adams, Louise Allen, Christopher Anderson, Karen Ansell, Samira Anwar, Isabel Ash, Jane Ashworth, Sher Aslam, Majunath Astagi, Colin Ball, Rajesh Balu, Victoria Barrett, Zahabiyah Bassi, Adam Bates, Dushyant Batra, Sarah Bell, Linda Belmour, James Benzimra, Ginny Birrell, Susmito Biswas, Andrew Blaikie, Michael Blundell, Kate Bolton, Ewoud Bos, Pamela Bowen, Richard Bowman, Natalie Boyle, John Bradbury, Maria Bredow, Marsel Bregu, Nicholas Brennan, Rosie Brennan, Paul Brittain, Charles Buchanan, Catey Bunce, Howard Bunting, Priscilla Burgess, Cathie Burke, Alexandra Kate Bush, Jeremy Butcher, Lucilla Butler, Clare Cane, Cathryn Chadwick, Ruth Charlton, Anne-Marie Childs, Jessy Choi, Vivi Choleva, Amanda Churchill, Michael Clarke, Peter Clayton, Luke Clifford, Alan Connor, Rachel Cox, Lyn Cresswell, Annegret Dahlmann-Noor, Angela D'Amore, Mehul Dattani, Fiona Dean, Anita Devlin, Luna Dhir, Cora Doherty, Suzanne Dorey, Fiona Drimmie, Tina Duke, Gordon Dutton, Fiona Eaton, Megan Eaton, Danielle Eckersley, Clive Edelsten, Rachel Elderkin, Julia Ennis, Julia Escardo-Paton, Ziad Estephen, Onajite Etuwewe, Anthony Evans, Adjoa Ezekwe, Jenny Fairfield, Kevin Falzon, Allison Ferguson, Brian Fleck, Mary Gainsborough, Alexandra Galloway, Naomi Gerson-Sofer, Caspar Gibbon, Patricia Gibson, Kevin Goss, Katherine Graham-Evans, Judith Gray, Anna Gregory, Arun Gulati, Deniz Gurtin-Zorkun, Emma Guy, Diab Haddad, Helen Haggerty, Paul Haigh, Julia Hale, Samer Hamada, Joanne Hancox, Kerry Hanna, Sian Harris, Christine Harrison, Phillip Harvey, Sophie Headland, Dominic Heath, Paul Heaton, Robert Henderson, Melanie Hingorani, Zoe Hirst, Claire Hogg, Wolfgang Hogler, Roger Holden, Janice Hoole, Karen Horridge, Delyth Howard, Rachel Howells, Vanessa Irvine, Clare Irving, Nicola Johnson, Ian Johnston, Alice Jollands, David Jones, Annie Joseph, Archana Joshi, Pugazhvendan Kandaswamy, Charles Kattakayam, Joseph Keenan, Anne Kelly, James Kersey, Awais Khan, Peng Khaw, Tina Kipioti, Sadia Kiran, Lesley Kneen, Ajay Kotagiri, Richa Kulshrestha, Rosemary Lambley, Tim Lavy, Joanna Lawson, Vicki Lee, Jane Leitch, Julie Lennon, Gabi Lipshen, Chris Lloyd, John Loftus, Tom Lomas, Vernon Long, Jane Mackinnon, Mary MacRae, Usman Mahmood, Anna Maino, Sarah Maling, David Mansfield, Elizabeth Marder, Richard Markham, Jane Marr, Catherine Marsh, Anna Maw, Eleanor McCartney, Helen McCullagh, Anna McDonald, Derek McPhee, Lawrence Miall, Shila Mistry, Benjamin Moate, Meyyammai Mohan, Helen Moore, Will Moore, Nicola Morgan, Claire Morton, Alan Mulvihill, Ranjit Nair, Bill Newman, Christiane Nitsch, Katy O'Connell, Ngozi Oluonye, Vittaldas Pai, Helen Palmer, Maria Papadopoulos, Shelagh Parkinson, Bina Parmar, Manoj Parulekar, Madhavi Parvathareddy, Dipesh Patel, Himanshu Patel, Kamal Patel, Philippa Pennefather, Flaudia Petrone, Marcus Pierrepoint, Rachel Pilling, Sally Pollard, Renata Puertas, Karen Pysden, Anthony Quinn, Philip Quinn, Diyaa Rachdan, Jyoti Raina, Saul Rajak, Laura Ramm, Catherine Rands, Tekki Rao, Mary Ray, Ashwin Reddy, Sheilla Reilly, Maralla Rekha, Greg Richardson, Andrew Riordan, Nerys Roberts, Helen Robertson, Gillian Robinson, Neil Rogers, Shakir Saeed, Caroline Salmon, Jenefer Sargent, Nagini Sarvananthan, Conrad Schmoll, James Self, P Sellar, Elaine Service, Ayad Shafiq, Shilpa Shah, Vinod Sharma, Jemima Sharp, Julia Shaw, Manjula Shenoy, Tamsin Sleep, Elisa Smit, Katherine Smyth, Lynne Speedwell, Katherine Spowart, P Standring, Paulo Stanga, Alison Stanley, Alan Stanton, David Steel, John Stephen, Catherine Stewart, Jessica Street, Sally Stucke, Shona Sutherland, Katya Tambe, Anamika Tandon, Alison Tappin, Kate Taylor, Robert Taylor, Katherine Teasdale, Maria Theodorou, Gareth Thomas, Megan Thomas, Paula Thomas, Dorothy Thompson, Stephen Thomson, Indrajit Thopte, Peter Tiffin, Angela Tillett, Heidi Traunecker, Maria Tsimpida, Vivienne Van Someren, Udupa Venkatesh, Zoe Vermaak, Michael Vincent, David Walker, Simon Walker, Deidre Walsh, Bronwyn Walters, Martin Ward Platt, Louise Watson, Patrick Watts, Siobhan West, Stephanie West, Cathy White, Joy White, Gabriel Whitlingum, Cathy Williams, Sophie Wilne, Janice Wilson, Chien Wong, Tamsin Woodbridge, Paul Wright, Martha Wyles, and Philip Wylie

Subjects
Male, medicine.medical_specialty, Pediatrics, Adolescent, genetic structures, Cross-sectional study, Visual impairment, Vision Disorders, Blindness, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, Epidemiology, Health care, Ethnicity, Developmental and Educational Psychology, medicine, Humans, Cumulative incidence, 030212 general & internal medicine, Child, business.industry, Incidence, Incidence (epidemiology), Infant, Newborn, Childhood blindness, Infant, medicine.disease, United Kingdom, eye diseases, Cross-Sectional Studies, Socioeconomic Factors, Child, Preschool, Pediatrics, Perinatology and Child Health, Female, Observational study, medicine.symptom, business
Abstract

Summary Background The WHO VISION 2020 global initiative against blindness, launched in 2000, prioritised childhood visual disability by aiming to end avoidable childhood blindness by 2020. However, progress has been hampered by the global paucity of epidemiological data concerning childhood visual disability. The British Childhood Visual Impairment and Blindness Study 2 (BCVIS2) was done to address this evidence gap. Methods BCVIS2 was a prospective UK-wide, cross-sectional, observational study to establish an inception cohort of children newly diagnosed with visual impairment. Ophthalmologists and paediatricians reported cases from 89 hospitals and community centres across the UK. We included children aged 18 years or younger who were newly diagnosed with any condition causing impaired visual acuity to a level of 0·5 logMAR or worse (worse than 6/18 Snellen) in each eye, or equivalent vision as assessed by standard qualitative measures, between Oct 1, 2015, and Nov 1, 2016. Eligible children were notified simultaneously but independently by their managing ophthalmologists and paediatricians via the two national active surveillance schemes, the British Ophthalmological Surveillance Unit and the British Paediatric Surveillance Unit. Standardised detailed demographic, socioeconomic, and clinical data about detection, management, and treatment were collected at diagnosis and 1 year later. We calculated incidence estimates and relative rates by key sociodemographic factors. We did descriptive analyses of underlying ophthalmic disorders and non-ophthalmic comorbidities. Findings 61 (7%) of 845 eligible children initially notified were ineligible at follow-up because of improved vision after treatment. Thus, the study sample comprised 784 children with permanent newly-diagnosed all-cause visual impairment, severe visual impairment, or blindness. 559 (72%) of 778 children had clinically significant non-ophthalmic impairments or conditions. 28 (4%) of 784 children died within a year after diagnosis of visual disability (all had underlying systemic disorders). Incidence of visual disability in the first year of life was 5·19 per 10 000 children (95% CI 4·71–5·72), almost ten times higher than among 1-to-4-year-olds and between 20 times and 100 times higher than in the older age groups. The overall cumulative incidence (or lifetime risk) of visual impairment, severe visual impairment, or blindness was 10·03 per 10 000 children (9·35–10·76). Incidence rates were higher for those from any ethnic minority group, the lowest quintile of socioeconomic status, and those born preterm or with low birthweight. 345 (44%) of 784 children had a single affected anatomical site. Disorders of the brain and visual pathways affected 378 (48%) of 784 children. Interpretation BCVIS2 provides a contemporary snapshot of the heterogeneity, multi-morbidity, and vulnerability associated with childhood visual disability in a high-income country. These findings could facilitate developing and delivering health care and planning of interventional research. Our findings highlight the importance of including childhood visual disability as a sentinel event and metric in global child health initiatives. Funding Fight for Sight, National Institute for Health Research, and Ulverscroft Foundation.

Published
2021
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24. Mutations in thyroid hormone receptor α1 cause premature neurogenesis and progenitor cell depletion in human cortical development

Author

Chris A. Clark, Adam Kuczynski, David G. Gadian, Wui K. Chong, Erik Schoenmakers, Francesco Muntoni, Teresa G Krieger, Carla Moran, Faraneh Varga-Khadem, Krishna K Chatterjee, Frederick J. Livesey, Greta Lyons, W. Edward Visser, Benjamin D. Simons, Alberto Frangini, Alexandra Efthymiadou, Mehul Dattani, Internal Medicine, Schoenmakers, Erik [0000-0003-0674-8282], Simons, Benjamin [0000-0002-3875-7071], Chatterjee, Krishna [0000-0002-2654-8854], Livesey, Frederick [0000-0001-6128-3372], and Apollo - University of Cambridge Repository

Subjects
Microcephaly, Medical Sciences, Adolescent, Neurogenesis, Induced Pluripotent Stem Cells, Mutant, iPSCs, brain development, Biology, Corrections, 03 medical and health sciences, 0302 clinical medicine, Directed differentiation, Neural Stem Cells, Cell Adhesion, medicine, Humans, Progenitor cell, Child, Induced pluripotent stem cell, Cell Proliferation, 030304 developmental biology, 0303 health sciences, Multidisciplinary, Thyroid hormone receptor, Cell Differentiation, Biological Sciences, Middle Aged, Cell cycle, medicine.disease, thyroid hormone, 3. Good health, Cell biology, PNAS Plus, Mutation, Forebrain, Female, 030217 neurology & neurosurgery, Thyroid Hormone Receptors alpha
Abstract

Significance Thyroid hormone deficiencies are the most common preventable causes of intellectual disability. We report that mutations in the thyroid hormone receptor α1 gene (THRA) that result in intellectual disability also reduce brain size. Using human THRA mutation stem cell models, we studied the impact of THRA mutations on human brain development by combining quantitative lineage analysis, gene expression analyses, and novel assays of neuroepithelium formation. We found that THRA regulates the balance between progenitor self-renewal and neurogenesis, and thus overall brain size. Importantly, these in vitro results are consistent with in vivo evidence from magnetic resonance imaging of people with these mutations, advancing our understanding of thyroid hormone action in human brain development., Mutations in the thyroid hormone receptor α 1 gene (THRA) have recently been identified as a cause of intellectual deficit in humans. Patients present with structural abnormalities including microencephaly, reduced cerebellar volume and decreased axonal density. Here, we show that directed differentiation of THRA mutant patient-derived induced pluripotent stem cells to forebrain neural progenitors is markedly reduced, but mutant progenitor cells can generate deep and upper cortical layer neurons and form functional neuronal networks. Quantitative lineage tracing shows that THRA mutation-containing progenitor cells exit the cell cycle prematurely, resulting in reduced clonal output. Using a micropatterned chip assay, we find that spatial self-organization of mutation-containing progenitor cells in vitro is impaired, consistent with down-regulated expression of cell–cell adhesion genes. These results reveal that thyroid hormone receptor α1 is required for normal neural progenitor cell proliferation in human cerebral cortical development. They also exemplify quantitative approaches for studying neurodevelopmental disorders using patient-derived cells in vitro.

Published
2019
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25. RF13 | PMON48 A novel missense variant in the gene encoding Fatty Acid Synthase (FASN) associated with a unique multi-system disorder including hypopituitarism and hypoparathyroidism

Author

Mehul Dattani, Simon Eaton, Louise Gregory, and Steven Krywawych

Subjects
Endocrinology, Diabetes and Metabolism
Abstract

A male patient presented with a unique complex phenotype including panhypopituitarism, short stature with failure to respond to GH [IGF-1 generation test: no response to 2.8 mg/m2/day GH], sensorineural deafness, hypoparathyroidism, retinal dystrophy, and intellectual disability. He was 127cm tall at the age of 21 and was completely prepubertal (LH 0.8 U/L, FSH 2.6 U/L, Testosterone Exome sequencing and subsequent variant calling on this patient revealed a novel heterozygous de novo missense variant (c.6395C>T, p.A2132V) at a highly conserved residue in FASN encoding Fatty Acid Synthase. The variant was not present in any control database, including the GnomAD browser. Human embryonic brain expression analysis using in situ hybridisation, revealed FASN mRNA transcript staining in the diencephalon and hypothalamus at Carnegie stages (CS) 16, 19, 20 and 23, and in Rathke's pouch (primordium of the anterior pituitary) at CS16 only. Fatty acid synthase (FASN), a crucial multienzyme with seven different catalytic activities, converts acetyl-CoA and malonyl-CoA into long-chain saturated fatty acids such as palmitate, in the presence of NADPH. Murine null mutant Fasn-/- embryos die before implantation and Fasn+/- embryos at various stages in the early postnatal period. Fasn is expressed in multiple tissues including the brain, parathyroids, liver and adrenal. Biochemical investigation of the patient revealed high triglyceride concentrations (3.81-6.49 mmol/L; NR 0.38-2) at all time points during an 18 hour fast. He mobilised free fatty acids but did not generate an increase in 3-hydroxybutyrate, suggesting a defect in fatty acid oxidation or ketone body synthesis. He maintained normoglycaemia with normal hormone responses to fasting, except for an undetectable IGF-1 ( We measured de novo fatty acid synthesis in cultured patient and control fibroblast cells with 13C-Glucose, with and without the C75 fatty acid synthase inhibitor. Cell pellets were collected at three time-points, and 13C-fatty acids derived from 13C-glucose were analysed by mass spectrometry. Preliminary data showed that more C13-glucose was incorporated into de novo synthesised palmitic acid in control cells, suggesting reduced fatty acid synthesis in the patient. Our data suggest that FASN p.A2132V is pathogenic and contributed significantly to the complex patient phenotype, consistent with recent studies suggesting that neural stem/progenitor cells (NSPCs) in the rodent brain are governed by Fasn-dependent de novo lipogenesis for proliferation. Presentation: Sunday, June 12, 2022 12:36 p.m. - 12:41 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Published
2022
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26. PMON336 Pfizer Registry of Outcomes in Growth hormone RESearch (PROGRES): A multi-country, non-interventional, prospective, cohort study of patients receiving human growth hormone treatments under routine clinical care

Author

Mitchell E Geffner, Lourdes Ibanez, Aristides Maniatis, Daria L Torre, Carol Huang, Feyza Darendelieler, Mehul Dattani, Mohamad Maghnie, Moshe Phillip, Jovanna Dahlgren, Reiko Horikawa, Roy Gomez, Scott P Kelly, and Michael P Wajnrajch

Subjects
Endocrinology, Diabetes and Metabolism
Abstract

Background Children with growth hormone deficiency (GHD) are treated with recombinant human growth hormone (rhGH), usually administered as a daily subcutaneous injection. Long-acting hGH (LAGH) treatments (approved and in development) have the potential to improve adherence and treatment outcomes. Somatrogon is a LAGH currently being developed as a once-weekly injectable treatment for GHD. The Pfizer Registry of Outcomes in Growth hormone RESearch (PROGRES) study was initiated to assess the long-term safety and effectiveness of Genotropin and other hGH formulations to treat GHD under routine clinical care. Goals & aims: The overall goal of the registry is to increase our understanding of hGH treatments as used in a real-world setting. Enrolling children treated with different daily hGH brands as well as somatrogon (if approved in a given geography) will enable comparison between daily and LAGH, and across daily hGH brands. The primary objectives of the study are to describe and compare the safety and effectiveness of daily and LAGH treatments in children. Secondary objectives include evaluating adherence to hGH treatments and the health-related quality of life (HRQoL) and treatment experience of patients receiving hGH treatments. Methods For this non-interventional, prospective, phase 4 cohort study, eligible patients (male or female at any age) from >20 countries are planned for inclusion, with the aim of targeting 667 patients across the daily hGH brands in each of the three geographic regions. Patients will be enrolled from September 2021 to October 2029, with data collection planned until October 2030. Study inclusion criteria include prescription of daily Genotropin or other approved hGH treatments for GHD and the provision of informed consent/assent. If somatrogon is approved by regulatory agencies, somatrogon-treated patients will also be eligible for inclusion. Patients participating in any interventional clinical trials at the time of enrollment will be excluded from the study. Patients will be followed until the end of the study, withdrawal of consent, death, switch to an excluded hGH, or loss to follow-up, whichever occurs first. In addition to demographic and clinical characteristics, information on hGH treatment brand, dose and start/end dates will be collected, along with reasons for switching or discontinuing treatment. Primary safety outcomes include adverse events (AEs), serious AEs, and AEs of special interest. Primary effectiveness outcomes include annual height velocity (HV) and change in HV standard deviation scores. Treatment adherence, compliance outcomes, HRQoL, and patient treatment experience will be assessed. Conclusions The findings from the PROGRES study will provide valuable insights into the use of somatrogon, Genotropin and other approved hGH treatments in real-world clinical practice, specifically with regard to the long-term safety and effectiveness of these treatments as well as treatment compliance and patient HRQoL. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Published
2022
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27. Paediatric Endocrinology : Management of Endocrine Disorders in Children and Adolescents

Author

Mehul Dattani, Mohamad Maghnie, Mehul Dattani, and Mohamad Maghnie

Subjects
Pediatric endocrinology
Abstract

Pediatric Endocrinology covers all of the main aspects of translational endocrinology and clinical practice, making it an ideal resource for both paediatricians and endocrinologists. The book emphasizes the newer translational aspects of the topics covered, as well as molecular advances in diagnosis and therapy, although clinical relevance, with a particular focus on evidence-based clinical management, remains paramount. Further, transitions from childhood to adolescence and adulthood are discussed wherever appropriate. Written by a combination of respected and emerging experts in the field, this book is intended to serve as a major reference work for pediatric endocrinologists at all stages of their careers, as well as general pediatricians with an interest in endocrinology and diabetes, and endocrinologists in adult practice who may also treat children and adolescents. The book is part of the SpringerReference program, which provides access to ‘living editions'thatare constantly updated using a dynamic peer-review publishing process.

Published
2024

28. Genetic testing in inherited endocrine disorders: joint position paper of the European reference network on rare endocrine conditions (Endo-ERN)

Author

Eggermann T., Elbracht M., Kurth I., Juul A., Johannsen T. H., Netchine I., Mastorakos G., Johannsson G., Musholt T. J., Zenker M., Prawitt D., Pereira A. M., Hiort O., Stefan Riedl, Birgit Rami-Merhar, Greisa Vila, Sabina Baumgartner-Parzner, Walter Bonfig, Claudine Heinrichs, Dominique Maiter, Inge Gies, Martine Cools, Kristina Casteels, Albert Beckers, Sabina Zacharieva, Violeta Iotova, Tomislav Jukic, Dario Rahelic, Vassos Neocleous, Leonidas Phylactou, Michal Krsek, Jan Lebl, Claus Gravholt, Anders Juul, Vallo Tillmann, Vallo Volke, Tapani Ebeling, Thierry Brue, Patrice Rodien, Jérôme Bertherat, Christine Poitou Bernert, Philippe Touraine, Philippe Chanson, Michel Polak, Maithe Tauber, Thomas Eggermann, Joachim Spranger, Dagmar Fuhrer, Thomas Danne, Olaf Hiort, Klaus Mohnike, Dirk Prawitt, Markus Luster, Nicole Reisch, Martin Reincke, Julia Rohayem, Martin Fassnacht, Miklós Tóth, Alessandra Cassio, Sonia Toni, Csilla Krausz, Barbara Piccini, Diego Ferone, Gianni Russo, Luca Persani, Annamaria Colao, Mariacarolina Salerno, Marco Boscaro, Carla Scaroni, Ferruccio Santini, Giovanni Ceccarini, Ezio Ghigo, Iveta Dzivite-Krisane, Vita Rovite, Lauma Janozola, Rasa Verkauskiene, Michael Witsch, James Clark, Johannes Romijn, Thera Links, Nienke Biermasz, Sabine Hannema, Bas Havekes, Hedi Claahsen-van der Grinten, Henri Timmers, Robin Peeters, Gerlof Valk, A A Verrijn Stuart, Harm Haak, Eystein Husebye, Jens Bollerslev, Barbara Jarzab, Agnieszka 'Szypowska, João-Filipe Raposo, Dana Craiu, Doina Piciu, Ludmila Kostalova, Jarmila Vojtková, Tadej Battelino, Roque Cardona-Hernandez, Diego Yeste, Sonia Gaztambide, Anna Nordenström, Neil Gittoes, Trevor Cole, Elizabeth Crowne, Faisal Ahmed, Mohammed Didi, Marta Korbonits, Mehul Dattani, Peter Clayton, Justin Davies, Eggermann, T., Elbracht, M., Kurth, I., Juul, A., Johannsen, T. H., Netchine, I., Mastorakos, G., Johannsson, G., Musholt, T. J., Zenker, M., Prawitt, D., Pereira, A. M., Hiort, O, Salerno, M, Clinical sciences, Growth and Development, Pediatrics, Eggermann T., Elbracht M., Kurth I., Juul A., Johannsen T.H., Netchine I., Mastorakos G., Johannsson G., Musholt T.J., Zenker M., Prawitt D., Pereira A.M., and Hiort O., Stefan Riedl, Birgit Rami-Merhar, Greisa Vila, Sabina Baumgartner-Parzner, Walter Bonfig, Claudine Heinrichs, Dominique Maiter, Inge Gies, Martine Cools, Kristina Casteels, Albert Beckers, Sabina Zacharieva, Violeta Iotova, Tomislav Jukic, Dario Rahelic, Vassos Neocleous, Leonidas Phylactou, Michal Krsek, Jan Lebl, Claus Gravholt, Anders Juul, Vallo Tillmann, Vallo Volke, Tapani Ebeling, Thierry Brue, Patrice Rodien, Jérôme Bertherat, Christine Poitou Bernert, Philippe Touraine, Philippe Chanson, Michel Polak, Maithe Tauber, Thomas Eggermann, Joachim Spranger, Dagmar Fuhrer, Thomas Danne, Olaf Hiort, Klaus Mohnike, Dirk Prawitt, Markus Luster, Nicole Reisch, Martin Reincke, Julia Rohayem, Martin Fassnacht, Miklós Tóth, Alessandra Cassio, Sonia Toni, Csilla Krausz, Barbara Piccini, Diego Ferone, Gianni Russo, Luca Persani, Annamaria Colao, Mariacarolina Salerno, Marco Boscaro, Carla Scaroni, Ferruccio Santini, Giovanni Ceccarini, Ezio Ghigo, Iveta Dzivite-Krisane, Vita Rovite, Lauma Janozola, Rasa Verkauskiene, Michael Witsch, James Clark, Johannes Romijn, Thera Links, Nienke Biermasz, Sabine Hannema, Bas Havekes, Hedi Claahsen-van der Grinten, Henri Timmers, Robin Peeters, Gerlof Valk, A A Verrijn Stuart, Harm Haak, Eystein Husebye, Jens Bollerslev, Barbara Jarzab, Agnieszka 'Szypowska, João-Filipe Raposo, Dana Craiu, Doina Piciu, Ludmila Kostalova, Jarmila Vojtková, Tadej Battelino, Roque Cardona-Hernandez, Diego Yeste, Sonia Gaztambide, Anna Nordenström, Neil Gittoes, Trevor Cole, Elizabeth Crowne, Faisal Ahmed, Mohammed Didi, Marta Korbonits, Mehul Dattani, Peter Clayton, Justin Davies

Subjects
0301 basic medicine, Genetic testing, disorders of sex development, PREDICTION, lcsh:Medicine, CHILDREN, Review, VARIANTS, Hypogonadotropic hypogonadism, Imprinting disorder, 0302 clinical medicine, Pharmacology (medical), Genetics (clinical), Imprinting disorders, Rare endocrine conditions, Short stature - glucose and insulin homeostasis - Hypogonadotropic hypogonadism - differences/disorders of sex development, Medicine(all), RISK, medicine.diagnostic_test, CHALLENGES, differences, High-Throughput Nucleotide Sequencing, General Medicine, genetic testing, Imprinting disorders, Rare endocrine conditions, Short stature, glucose and insulin homeostasis, Hypogonadotropic hypogonadism, disorders of sex development, Mutation (genetic algorithm), Rare endocrine condition, Identification (biology), Genetic counseling, 030209 endocrinology & metabolism, Computational biology, DIAGNOSIS, Endocrine System Diseases, differences/disorders of sex development, 03 medical and health sciences, Rare Diseases, BECKWITH-WIEDEMANN SYNDROME, medicine, MANAGEMENT, Endocrine system, Humans, business.industry, Network on, lcsh:R, glucose and insulin homeostasis, Human genetics, Short stature, 030104 developmental biology, Mutation, Position paper, business, Short stature - glucose and insulin homeostasis
Abstract

Orphanet journal of rare diseases: OJRD 15(1), 144 (2020). doi:10.1186/s13023-020-01420-w, Published by BioMed Central, London

Published
2020
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29. Bayesian Inference Associates Rare KDR Variants with Specific Phenotypes in Pulmonary Arterial Hypertension

Author

Emilia M. Swietlik, Daniel Greene, Na Zhu, Karyn Megy, Marcella Cogliano, Smitha Rajaram, Divya Pandya, Tobias Tilly, Katie A. Lutz, Carrie C.L. Welch, Michael W. Pauciulo, Laura Southgate, Jennifer M. Martin, Carmen M. Treacy, Christopher J. Penkett, Jonathan C. Stephens, Harm J. Bogaard, Colin Church, Gerry Coghlan, Anna W. Coleman, Robin Condliffe, Christina A. Eichstaedt, Mélanie Eyries, Henning Gall, Stefano Ghio, Barbara Girerd, Ekkehard Grünig, Simon Holden, Luke Howard, Marc Humbert, David G. Kiely, Gabor Kovacs, Jim Lordan, Rajiv D. Machado, Robert V. MacKenzie Ross, Colm McCabe, Shahin Moledina, David Montani, Horst Olschewski, Joanna Pepke-Zaba, Laura Price, Christopher J. Rhodes, Werner Seeger, Florent Soubrier, Jay Suntharalingam, Mark R. Toshner, Anton Vonk Noordegraaf, John Wharton, James M. Wild, Stephen John Wort, Allan Lawrie, Martin R. Wilkins, Richard C. Trembath, Yufeng Shen, Wendy K. Chung, Andrew J. Swift, William C. Nichols, Nicholas W. Morrell, Stefan Gräf, Stephen Abbs, Lara Abulhoul, Julian Adlard, Munaza Ahmed, Timothy J. Aitman, Hana Alachkar, David J. Allsup, Philip Ancliff, Richard Antrobus, Ruth Armstrong, Gavin Arno, Sofie Ashford, William J. Astle, Anthony Attwood, Paul Aurora, Christian Babbs, Chiara Bacchelli, Tamam Bakchoul, Siddharth Banka, Tadbir Bariana, Julian Barwell, Joana Batista, Helen E. Baxendale, Phil L. Beales, David L. Bennett, Agnieszka Bierzynska, Tina Biss, Maria A.K. Bitner-Glindzicz, Graeme C. Black, Marta Bleda, Iulia Blesneac, Detlef Bockenhauer, Sara Boyce, John R. Bradley, Gerome Breen, Paul Brennan, Carole Brewer, Matthew Brown, Andrew C. Browning, Michael J. Browning, Rachel J. Buchan, Matthew S. Buckland, Teofila Bueser, Carmen Bugarin Diz, John Burn, Siobhan O. Burns, Oliver S. Burren, Nigel Burrows, Carolyn Campbell, Gerald Carr-White, Keren Carss, Ruth Casey, Mark J. Caulfield, Jenny Chambers, John Chambers, Melanie M.Y. Chan, Floria Cheng, Patrick F. Chinnery, Manali Chitre, Martin T. Christian, Jill Clayton-Smith, Maureen Cleary, Naomi Clements Brod, Elizabeth Colby, Trevor R.P. Cole, Janine Collins, Peter W. Collins, Cecilia J. Compton, H. Terence Cook, Stuart Cook, Nichola Cooper, Paul A. Corris, Nicola S. Curry, Matthew J. Daniels, Mehul Dattani, Louise C. Daugherty, John Davis, Anthony De Soyza, Sri V.V. Deevi, Timothy Dent, Charu Deshpande, Eleanor F. Dewhurst, Peter H. Dixon, Sofia Douzgou, Kate Downes, Anna M. Drazyk, Elizabeth Drewe, Daniel Duarte, Tina Dutt, J. David M. Edgar, Karen Edwards, William Egner, Melanie N. Ekani, Perry Elliott, Wendy N. Erber, Marie Erwood, Maria C. Estiu, Dafydd Gareth Evans, Gillian Evans, Tamara Everington, Hiva Fassihi, Remi Favier, Debra Fletcher, Frances A. Flinter, R. Andres Floto, Tom Fowler, James Fox, Amy J. Frary, Courtney E. French, Kathleen Freson, Mattia Frontini, Abigail Furnell, Daniel P. Gale, Vijeya Ganesan, Michael Gattens, Hossein-Ardeschir Ghofrani, J. Simon R. Gibbs, Kate Gibson, Kimberly C. Gilmour, Nicholas S. Gleadall, Sarah Goddard, Keith Gomez, Pavels Gordins, David Gosal, Jodie Graham, Luigi Grassi, Lynn Greenhalgh, Andreas Greinacher, Paolo Gresele, Philip Griffiths, Sofia Grigoriadou, Detelina Grozeva, Mark Gurnell, Scott Hackett, Charaka Hadinnapola, Rosie Hague, William M. Hague, Matthias Haimel, Matthew Hall, Helen L. Hanson, Eshika Haque, Kirsty Harkness, Andrew R. Harper, Claire L. Harris, Daniel Hart, Ahamad Hassan, Grant Hayman, Alex Henderson, Archana Herwadkar, Jonathan Hoffman, Rita Horvath, Henry Houlden, Arjan C. Houweling, Fengyuan Hu, Gavin Hudson, Aarnoud P. Huissoon, Matthew Hurles, Melita Irving, Louise Izatt, Roger James, Sally A. Johnson, Stephen Jolles, Jennifer Jolley, Dragana Josifova, Neringa Jurkute, Mary A. Kasanicki, Hanadi Kazkaz, Rashid Kazmi, Peter Kelleher, Anne M Kelly, Wilf Kelsall, Carly Kempster, Nathalie Kingston, Nils Koelling, Myrto Kostadima, Ania Koziell, Roman Kreuzhuber, Taco W. Kuijpers, Ajith Kumar, Dinakantha Kumararatne, Manju A. Kurian, Michael A. Laffan, Fiona Lalloo, Michele Lambert, Hana Lango Allen, D. Mark Layton, Claire Lentaigne, Tracy Lester, Adam P. Levine, Rachel Linger, Hilary Longhurst, Lorena E. Lorenzo, Eleni Louka, Paul A. Lyons, Bella Madan, Eamonn R. Maher, Jesmeen Maimaris, Samantha Malka, Sarah Mangles, Rutendo Mapeta, Kevin J. Marchbank, Stephen Marks, Hugh S. Markus, Hanns-Ulrich Marschall, Andrew Marshall, Mary Mathias, Emma Matthews, Heather Maxwell, Paul McAlinden, Mark I. McCarthy, Harriet McKinney, Stuart Meacham, Adam J. Mead, Sarju G. Mehta, Michel Michaelides, Carolyn Millar, Shehla N. Mohammed, Anthony T. Moore, Monika Mozere, Keith W. Muir, Andrew D. Mumford, Andrea H. Nemeth, William G. Newman, Michael Newnham, Sadia Noorani, Paquita Nurden, Jennifer O’Sullivan, Samya Obaji, Chris Odhams, Steven Okoli, Andrea Olschewski, Kai Ren Ong, S. Helen Oram, Elizabeth Ormondroyd, Willem H. Ouwehand, Claire Palles, Sofia Papadia, Soo-Mi Park, David Parry, Smita Patel, Joan Paterson, Andrew Peacock, Simon H. Pearce, Kathelijne Peerlinck, Romina Petersen, Clarissa Pilkington, Kenneth E.S. Poole, Bethan Psaila, Angela Pyle, Richard Quinton, Shamima Rahman, Anupama Rao, F. Lucy Raymond, Paula J. Rayner-Matthews, Augusto Rendon, Tara Renton, Andrew S.C. Rice, Alex Richter, Leema Robert, Irene Roberts, Sarah J. Rose, Robert Ross-Russell, Catherine Roughley, Noemi B.A. Roy, Deborah M. Ruddy, Omid Sadeghi-Alavijeh, Moin A. Saleem, Nilesh Samani, Crina Samarghitean, Alba Sanchis-Juan, Ravishankar B. Sargur, Robert N. Sarkany, Simon Satchell, Sinisa Savic, Genevieve Sayer, John A. Sayer, Laura Scelsi, Andrew M. Schaefer, Sol Schulman, Richard Scott, Marie Scully, Claire Searle, Arjune Sen, W.A. Carrock Sewell, Denis Seyres, Neil Shah, Olga Shamardina, Susan E. Shapiro, Adam C. Shaw, Keith Sibson, Lucy Side, Ilenia Simeoni, Michael A. Simpson, Matthew C. Sims, Suthesh Sivapalaratnam, Damian Smedley, Katherine R. Smith, Kenneth G.C. Smith, Katie Snape, Nicole Soranzo, Olivera Spasic-Boskovic, Simon Staines, Emily Staples, Hannah Stark, Kathleen E. Stirrups, Alex Stuckey, Petros Syrris, R. Campbell Tait, Kate Talks, Rhea Y.Y. Tan, Jenny C. Taylor, John M. Taylor, James E. Thaventhiran, Andreas C. Themistocleous, David Thomas, Ellen Thomas, Moira J. Thomas, Patrick Thomas, Kate Thomson, Adrian J. Thrasher, Chantal Thys, Marc Tischkowitz, Catherine Titterton, Cheng-Hock Toh, Ian P. Tomlinson, Matthew Traylor, Paul Treadaway, Salih Tuna, Ernest Turro, Philip Twiss, Tom Vale, Chris Van Geet, Natalie van Zuydam, Anthony M Vandersteen, Marta Vazquez-Lopez, Julie von Ziegenweidt, Annette Wagner, Quinten Waisfisz, Neil Walker, Suellen M. Walker, James S. Ware, Hugh Watkins, Christopher Watt, Andrew R. Webster, Lucy Wedderburn, Wei Wei, Steven B. Welch, Julie Wessels, Sarah K. Westbury, John-Paul Westwood, Deborah Whitehorn, James Whitworth, Andrew O.M. Wilkie, Catherine Williamson, Brian T. Wilson, Edwin K.S. Wong, Nicholas Wood, Yvette Wood, Christopher Geoffrey Woods, Emma R. Woodward, Austen Worth, Michael Wright, Katherine Yates, Patrick F.K. Yong, Timothy Young, Ping Yu, Patrick Yu-Wai-Man, Eliska Zlamalova, Russel Hirsch, R. James White, Marc Simon, David Badesch, Erika Rosenzweig, Charles Burger, Murali Chakinala, Thenappan Thenappan, Greg Elliott, Robert Simms, Harrison Farber, Robert Frantz, Jean Elwing, Nicholas Hill, Dunbar Ivy, James Klinger, Steven Nathan, Ronald Oudiz, Ivan Robbins, Robert Schilz, Terry Fortin, Jeffrey Wilt, Delphine Yung, Eric Austin, Ferhaan Ahmad, Nitin Bhatt, Tim Lahm, Adaani Frost, Zeenat Safdar, Zia Rehman, Robert Walter, Fernando Torres, Sahil Bakshi, Stephen Archer, Rahul Argula, Christopher Barnett, Raymond Benza, Ankit Desai, Veeranna Maddipati, University of Cambridge [UK] (CAM), Columbia University [New York], University of Sheffield [Sheffield], University of Cincinnati (UC), St George's, University of London, Vrije Universiteit Amsterdam [Amsterdam] (VU), Golden Jubilee National Hospital, Glasgow, Royal Free Hospital [London, UK], Heidelberg University Hospital [Heidelberg], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Technische Hochschule Mittelhessen - University of Applied Sciences [Giessen] (THM), Fondazione IRCCS Policlinico San Matteo, Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Universität Heidelberg [Heidelberg], Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Imperial College London, Royal Hallamshire Hospital, University of Graz, Freeman Hospital, Royal United Hospitals Bath (RUH), Great Ormond Street Hospital for Children [London] (GOSH), Royal Papworth Hospital, Cambridge Biomedical Campus, Cambridge, United Kingdom., King‘s College London, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Karl-Franzens-Universität [Graz, Autriche], Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Swietlik, Emilia [0000-0002-4095-8489], Megy, Karyn [0000-0002-2826-3879], Tilly, Tobias [0000-0002-6762-5342], Stephens, Jonathan [0000-0003-2020-9330], Toshner, Mark [0000-0002-3969-6143], Morrell, Nicholas [0000-0001-5700-9792], Graf, Stefan [0000-0002-1315-8873], Apollo - University of Cambridge Repository, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Karl-Franzens-Universität Graz, HAL-SU, Gestionnaire, British Heart Foundation, and The Academy of Medical Sciences

Subjects
0301 basic medicine, Candidate gene, Cardiac & Cardiovascular Systems, genetic association studies, 030204 cardiovascular system & hematology, Biology, Bayesian inference, 03 medical and health sciences, 0302 clinical medicine, Missing heritability problem, pulmonary hypertension, medicine, Family history, Gene, Genetics & Heredity, Genetics, family history, Science & Technology, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Kinase insert domain receptor, computed tomography, General Medicine, Original Articles, medicine.disease, Pulmonary hypertension, Phenotype, 3. Good health, 030104 developmental biology, Cardiovascular System & Cardiology, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Life Sciences & Biomedicine, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, vascular endothelial growth factor receptor
Abstract

Supplemental Digital Content is available in the text., Background: Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH, we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics. Methods: We analyzed 13 037 participants enrolled in the NBR study (NIHR BioResource—Rare Diseases), of which 1148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension, we used the Bayesian rare variant association method BeviMed. Results: Heterozygous, high impact, likely loss-of-function variants in the kinase insert domain receptor (KDR) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (posterior probability=0.989) and older age at diagnosis (posterior probability=0.912). We also provide evidence for familial segregation of a rare nonsense KDR variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the 5 patients harboring these predicted deleterious variants in KDR. Four additional PAH cases with rare likely loss-of-function variants in KDR were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. Conclusions: The Bayesian inference approach allowed us to independently validate KDR, which encodes for the VEGFR2 (vascular endothelial growth factor receptor 2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for KDR being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.

Published
2020
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30. Germ Line Mutations in the Thyroid Hormone Receptor Alpha Gene Predispose to Cutaneous Tags and Melanocytic Nevi

Author

Emery Di Cicco, Carla Moran, W.E. (Edward) Visser, Annarita Nappi, Erik Schoenmakers, Pamela Todd, Greta Lyons, Mehul Dattani, Raffaele Ambrosio, Silvia Parisi, Domenico Salvatore, Krishna Chatterjee, Monica Dentice, Emery Di Cicco, Carla Moran, W.E. (Edward) Visser, Annarita Nappi, Erik Schoenmakers, Pamela Todd, Greta Lyons, Mehul Dattani, Raffaele Ambrosio, Silvia Parisi, Domenico Salvatore, Krishna Chatterjee, and Monica Dentice

Abstract

Background: Many physiological effects of thyroid hormone (TH) are mediated by its canonical action via nuclear receptors (TH receptor α and β [TRα and TRβ]) to regulate transcription of target genes. Heterozygous dominant negative mutations in human TRα mediate resistance to thyroid hormone alpha (RTHα), characterized by features of hypothyroidism (e.g., skeletal dysplasia, neurodevelopmental retardation, constipation) in specific tissues, but near-normal circulating TH concentrations. Hitherto, 41 RTHα cases have been recorded worldwide. Methods: RTHα cases (n = 10) attending a single center underwent cutaneous assessment, recording skin lesions. Lesions excised from different RTHα patients were analyzed histologically and profiled for cellular markers of proliferation and oncogenic potential. Proliferative characteristics of dermal fibroblasts and inducible pluripotent stem cell (iPSC)-derived keratinocytes from patients and control subjects were analyzed. Results: Multiple skin tags and nevi were recorded in all cases, mainly in the head and neck area with a predilection for flexures. The affected patients had highly deleterious mutations (p.E403X, p.E403K, p.F397fs406X, p.A382PfsX7) involving TRα1 alone or mild/moderate loss-of-function mutations (p.A263V, p.L274P) common to TRα1 and TRα2 isoforms. In four patients, although lesions excised for cosmetic reasons were benign intradermal melanocytic nevi histologically, they significantly overexpressed markers of cell proliferation (K17, cyclin D1) and type 3 deiodinase. In addition, oncogenic markers typical of basal cell carcinoma (Gli-1, Gli-2, Ptch-1, n = 2 cases) and melanoma (c-kit, MAGE, CDK4, n = 1) were markedly upregulated in skin lesions. Cell cycle progression and proliferation of TRα mutation-containing dermal fibroblasts and iPSC-derived keratinocytes from patients were markedly increased. Conclusions: Our observations highlight frequent occurrence of skin tags and benign melanocytic nevi in RTHα

Published
2021
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34. Project to develop BSPED UK standardised guidelines for sex hormone priming and glucagon stimulation testing (GST) in children and adolescents

Author

Elizabeth Crowne, Peter Clayton, Christina Wei, Tabitha Randell, Mehul Dattani, and Pauline Musson

Subjects
medicine.medical_specialty, Sex hormone-binding globulin, Endocrinology, biology, business.industry, Internal medicine, biology.protein, Medicine, Glucagon stimulation, business, Priming (psychology)
Published
2019
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36. A 10 year experience of the management of severe hypocalcaemia associated with thymus transplantation in a United Kingdom tertiary centre

Author

Peter Hindmarsh, Helen Spoudeas, Catherine Peters, Jeremy Allgrove, Pratik Shah, Harshini Katugampola, Elena Monti, Katherine Taylor, Rakesh Amin, Caroline Brain, Mehul Dattani, and Nicole Goff

Subjects
Pediatrics, medicine.medical_specialty, Thymus transplantation, business.industry, medicine.medical_treatment, Medicine, Hypocalcaemia, business, medicine.disease
Published
2018
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38. Growth Hormone Research Society perspective on biomarkers of GH action in children and adults

Author

Gudmundur Johannsson, Martin Bidlingmaier, Beverly M K Biller, Margaret Boguszewski, Felipe F Casanueva, Philippe Chanson, Peter E Clayton, Catherine S Choong, David Clemmons, Mehul Dattani, Jan Frystyk, Ken Ho, Andrew R Hoffman, Reiko Horikawa, Anders Juul, John J Kopchick, Xiaoping Luo, Sebastian Neggers, Irene Netchine, Daniel S Olsson, Sally Radovick, Ron Rosenfeld, Richard J Ross, Katharina Schilbach, Paulo Solberg, Christian Strasburger, Peter Trainer, Kevin C J Yuen, Kerstin Wickstrom, Jens O L Jorgensen, and Internal Medicine

Subjects
medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Review, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Quality of life, Acromegaly, Internal Medicine, medicine, Clinical endpoint, Intensive care medicine, GH deficiency, business.industry, Surrogate endpoint, medicine.disease, Idiopathic short stature, GH, IGF-I, 030220 oncology & carcinogenesis, Pegvisomant, Life expectancy, Biomarker (medicine), acromegaly, business, medicine.drug
Abstract

Objective: The Growth Hormone Research Society (GRS) convened a Workshop in 2017 to evaluate clinical endpoints, surrogate endpoints and biomarkers during GH treatment of children and adults and in patients with acromegaly. Participants: GRS invited 34 international experts including clinicians, basic scientists, a regulatory scientist and physicians from the pharmaceutical industry. Evidence: Current literature was reviewed and expert opinion was utilized to establish the state of the art and identify current gaps and unmet needs. Consensus process: Following plenary presentations, breakout groups discussed questions framed by the planning committee. The attendees re-convened after each breakout session to share the group reports. A writing team compiled the breakout session reports into a document that was subsequently discussed and revised by participants. This was edited further and circulated for final review after the meeting. Participants from pharmaceutical companies were not part of the writing process. Conclusions: The clinical endpoint in paediatric GH treatment is adult height with height velocity as a surrogate endpoint. Increased life expectancy is the ideal but unfeasible clinical endpoint of GH treatment in adult GH-deficient patients (GHDA) and in patients with acromegaly. The pragmatic clinical endpoints in GHDA include normalization of body composition and quality of life, whereas symptom relief and reversal of comorbidities are used in acromegaly. Serum IGF-I is widely used as a biomarker, even though it correlates weakly with clinical endpoints in GH treatment, whereas in acromegaly, normalization of IGF-I may be related to improvement in mortality. There is an unmet need for novel biomarkers that capture the pleiotropic actions of GH in relation to GH treatment and in patients with acromegaly. Objective: The Growth Hormone Research Society (GRS) convened a Workshop in 2017 to evaluate clinical endpoints, surrogate endpoints and biomarkers during GH treatment of children and adults and in patients with acromegaly. Participants: GRS invited 34 international experts including clinicians, basic scientists, a regulatory scientist and physicians from the pharmaceutical industry. Evidence: Current literature was reviewed and expert opinion was utilized to establish the state of the art and identify current gaps and unmet needs. Consensus process: Following plenary presentations, breakout groups discussed questions framed by the planning committee. The attendees re-convened after each breakout session to share the group reports. A writing team compiled the breakout session reports into a document that was subsequently discussed and revised by participants. This was edited further and circulated for final review after the meeting. Participants from pharmaceutical companies were not part of the writing process. Conclusions: The clinical endpoint in paediatric GH treatment is adult height with height velocity as a surrogate endpoint. Increased life expectancy is the ideal but unfeasible clinical endpoint of GH treatment in adult GH-deficient patients (GHDA) and in patients with acromegaly. The pragmatic clinical endpoints in GHDA include normalization of body composition and quality of life, whereas symptom relief and reversal of comorbidities are used in acromegaly. Serum IGF-I is widely used as a biomarker, even though it correlates weakly with clinical endpoints in GH treatment, whereas in acromegaly, normalization of IGF-I may be related to improvement in mortality. There is an unmet need for novel biomarkers that capture the pleiotropic actions of GH in relation to GH treatment and in patients with acromegaly.

Published
2018
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44. Growth hormone neurosecretory dysfunction as part of the spectrum of growth hormone deficiency disorders which benefit from growth hormone treatment

Author

Claire Hughes, Mehul Dattani, Pratik Shah, Silvana Caiulo, Rakesh Amin, Catherine Peters, Hoong-Wei Gan, Peter Hindmarsh, and Helen Spoudeas

Subjects
Growth hormone treatment, medicine.medical_specialty, Growth Hormone Neurosecretory Dysfunction, Endocrinology, business.industry, Internal medicine, Medicine, business, medicine.disease, Growth hormone deficiency, Endocrine gland
Published
2017
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47. Rare variants in single-minded 1 (SIM1) are associated with severe obesity

Author

Shwetha, Ramachandrappa, Anne, Raimondo, Anna M G, Cali, Julia M, Keogh, Elana, Henning, Sadia, Saeed, Amanda, Thompson, Sumedha, Garg, Elena G, Bochukova, Soren, Brage, Victoria, Trowse, Eleanor, Wheeler, Adrienne E, Sullivan, Mehul, Dattani, Peter E, Clayton, Vipan, Datta, Vippan, Datta, John B, Bruning, Nick J, Wareham, Stephen, O'Rahilly, Daniel J, Peet, Ines, Barroso, Murray L, Whitelaw, and I Sadaf, Farooqi

Subjects
Male, Models, Molecular, Transcriptional Activation, Heterozygote, medicine.medical_specialty, Aryl hydrocarbon receptor nuclear translocator, Adolescent, DNA Mutational Analysis, Mutation, Missense, Gene Expression, 030209 endocrinology & metabolism, Biology, Energy homeostasis, 03 medical and health sciences, 0302 clinical medicine, Genes, Reporter, Internal medicine, Basic Helix-Loop-Helix Transcription Factors, medicine, Humans, Obesity, Child, Genetic Association Studies, Luciferases, Renilla, 030304 developmental biology, 2. Zero hunger, Genetics, 0303 health sciences, Infant, Heterozygote advantage, General Medicine, Penetrance, Body Height, Pedigree, Repressor Proteins, Melanocortin 4 receptor, HEK293 Cells, Endocrinology, Case-Control Studies, Child, Preschool, SIM1, Receptor, Melanocortin, Type 4, Female, Erratum, Melanocortin, Haploinsufficiency, Research Article
Abstract

Single-minded 1 (SIM1) is a basic helix-loop-helix transcription factor involved in the development and function of the paraventricular nucleus of the hypothalamus. Obesity has been reported in Sim1 haploinsufficient mice and in a patient with a balanced translocation disrupting SIM1. We sequenced the coding region of SIM1 in 2,100 patients with severe, early onset obesity and in 1,680 controls. Thirteen different heterozygous variants in SIM1 were identified in 28 unrelated severely obese patients. Nine of the 13 variants significantly reduced the ability of SIM1 to activate a SIM1-responsive reporter gene when studied in stably transfected cells coexpressing the heterodimeric partners of SIM1 (ARNT or ARNT2). SIM1 variants with reduced activity cosegregated with obesity in extended family studies with variable penetrance. We studied the phenotype of patients carrying variants that exhibited reduced activity in vitro. Variant carriers exhibited increased ad libitum food intake at a test meal, normal basal metabolic rate, and evidence of autonomic dysfunction. Eleven of the 13 probands had evidence of a neurobehavioral phenotype. The phenotypic similarities between patients with SIM1 deficiency and melanocortin 4 receptor (MC4R) deficiency suggest that some of the effects of SIM1 deficiency on energy homeostasis are mediated by altered melanocortin signaling.

Published
2013
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48. 5-alpha reductase deficiency: insights into the diagnosis and management of a rare condition

Author

Elim Man, Ieuan Hughes, Mehul Dattani, Charles Buchanan, James Greening, Gerard S. Conway, Helen L Storr, Helen Spoudeas, Khalid Hussain, Gill Rumsby, John Achermann, John Torpiano, Elena Monti, Caroline Brain, Imran Mushtaq, and Polly Carmichael

Subjects
medicine.medical_specialty, Endocrinology, business.industry, 5-Alpha-Reductase Deficiency, Internal medicine, medicine, business
Published
2016
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49. Primus-Eugen Mullis, MD (1954-2016)

Author

Mehul, Dattani, Annina, Mullis, and Primus-Eugen, Mullis

Subjects
Endocrinology, Humans, History, 20th Century, History, 21st Century, Pediatrics, Switzerland
Published
2016

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