SFEBES2015 Poster Presentations Pituitary (48 abstracts)
The founder R304* AIP mutation is prevalent in Irish acromegaly and gigantism patients as well as in the general population of Ireland
Serban Radian 1, , Yoan Diekmann 3 , Plamena Gabrovska 1 , Brendan Holland 1 , Lisa Bradley 4 , Helen Wallace 5 , Karen Stals 6 , Anna-Marie Bussell 6 , Karen McGurren 7 , Martin Cuesta 7 , Anthony W Ryan 8 , Maria Herincs 1 , Laura C Hernández-Ramírez 1 , Aidan Holland 1 , Jade Samuels 1 , Elena Daniela Aflorei 1 , Sayka Barry 1 , Judit Dénes 1 , Ida Pernicova 1 , Craig E Stiles 1 , Giampaolo Trivellin 1 , Ronan McCloskey 1 , Michal Ajzensztejn 9 , Noina Abid 9 , Scott A Akker 1 , Moises Mercado 10 , Mark Cohen 11 , Rajesh V Thakker 12 , Stephanie Baldeweg 13 , Ariel Barkan 14 , Madalina Musat 2 , Miles Levy 15 , Steve Orme 16 , Martina Unterländer 17 , Joachim Burger 17 , Ajith V Kumar 18 , Sian Ellard 6 , Joseph McPartlin 19 , Ross McManus 8 , Gerard J Linden 20 , Brew Atkinson 5 , Mark G Thomas 3 , David J Balding 3, , Amar Agha 7 , Chris J Thompson 7 , Steve J Hunter 5 , Patrick J Morrison 4, & Márta Korbonits 1
1Department of Endocrinology, Barts and the London School of Medicine, Queen Mary University of London, London, UK; 2Department of Endocrinology, “C. Davila” University of Medicine and Pharmacy and C.I Parhon National Institute of Endocrinology, Bucharest, Romania; 3Research Department of Genetics, Evolution and Environment, University College London, London, UK; 4Department of Medical Genetics, Belfast HSC Trust, Belfast, UK; 5Regional Centre for Endocrinology and Diabetes, Royal Victoria Hospital, Belfast, UK; 6Department of Molecular Genetics, Royal Devon and Exeter Foundation Trust, Exeter, UK; 7Department of Endocrinology and Diabetes, Beaumont Hospital/RCSI Medical School, Dublin, Ireland; 8Department of Clinical Medicine and Institute of Molecular Medicine, Trinity College Dublin, Trinity Centre for Health Sciences, St James’s Hospital, Dublin, Ireland; 9Royal Belfast Hospital for Sick Children, Belfast, UK; 10Endocrinology Service/Experimental Endocrinology Unit, Hospital de Especialidades, Centro Medico Nacional Siglo XXI, IMSS, Mexico City, Mexico; 11Barnet General Hospital, London, UK; 12Academic Endocrine Unit, University of Oxford, Oxford, UK; 13University College London Hospitals, London, UK; 14University of Michigan, Ann Arbor, MI, USA; 15Department of Endocrinology, University Hospitals of Leicester, Leicester, UK; 16Department of Endocrinology, St James’s University Hospital, Leeds, UK; 17Institute of Anthropology, Johannes Gutenberg University, Mainz, Germany; 18North East Thames Regional Genetics Service, Great Ormond Street Hospital, London,UK; 19Trinity Biobank, Institute of Molecular Medicine, Trinity College Dublin, Trinity Centre for Health Sciences, St James’s Hospital, Dublin, Ireland; 20Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, UK; 21Schools of Biosciences and of Mathematics & Statistics, University of Melbourne, Australia; 22Centre for Cancer Research and Cell Biology, Queens University Belfast, Belfast, UK.
Background: A founder mutated AIP allele, R304* was previously identified in several Irish familial isolated pituitary adenoma (FIPA) pedigrees from a small region within Mid Ulster, Northern Ireland, but the allele’s general population impact remains unknown.
Aims: To estimate R304* prevalence in the general population and pituitary adenoma (PA) patients and to calculate the allele’s time to most recent common ancestor (tMRCA).
Methods: We tested for AIP mutations 116 somatotrophinoma patients from the Belfast and Dublin endocrine tertiary referral centres and studied additional R304*-positive pedigrees from our international FIPA database (five Irish/five non-Irish). We genotyped three population samples from Mid Ulster (n=936), Greater Belfast (n=1000) and Republic of Ireland (ROI, n=2094). Based on AIP-centred microsatellite haplotypes, we estimated through coalescent-based simulation the R304* allele’s tMRCA and current number of allele carriers.
Results: R304* was very frequent in somatotrophinoma patients (12.6%/6.8% in Belfast/Dublin). General population prevalence estimates were 6/936 (95% CI: 0.0023–0.013; Mid Ulster), 1/1000 (95% CI: 0.000025–0.0055; Greater Belfast) and 0/2094 (95% CI: 0–0·0014; ROI). All 18 Irish pedigrees (two identified through population screening) shared a recent common ancestor, while the non-Irish pedigrees were independent from each other and from the Irish founder. The Irish pedigrees’ median tMRCA was 2550 years (95% CI: 1275–5000). Forward simulation predicted 144 allele carriers/generation (95% CI: 30–1725).
Conclusions: R304* has a clinically-relevant prevalence in Ireland, especially in Mid Ulster, due to an approximately 2500-year old founder ancestor. While 40 affected carriers have already been identified, we estimated through forward simulation that 86 PA cases are currently alive (95% CI: 18–1035). Although R304* population screening cannot be currently advocated, our data strongly support the testing of Irish-origin young-onset somatotrophinoma patients. Our study generated increased disease awareness locally, possibly leading to early diagnosis of these typically aggressive AIP-related PAs, crucial to their effective management.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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