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Tissue variations of mosaic genome-wide paternal uniparental disomy and phenotype of multi-syndromal congenital hyperinsulinism.

Authors
  • Christesen, Henrik Thybo1
  • Christensen, Lene Gaarsmand2
  • Löfgren, Åsa Mattsson3
  • Brøndum-Nielsen, Karen4
  • Svensson, Johan5
  • Brusgaard, Klaus6
  • Samuelsson, Sofie7
  • Elfving, Maria8
  • Jonson, Tord7
  • Grønskov, Karen4
  • Rasmussen, Lars9
  • Backman, Torbjörn10
  • Hansen, Lars Kjaersgaard11
  • Larsen, Annette Rønholt12
  • Petersen, Henrik13
  • Detlefsen, Sönke14
  • 1 Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark; Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark; Institute of Clinical Research, University of Southern Denmark Odense, Odense, Denmark. Electronic address: [email protected] , (Denmark)
  • 2 Dept. of Pathology, Odense University Hospital, Odense, Denmark. , (Denmark)
  • 3 Dept. of Paediatrics, Helsingborg Hospital, Sweden. , (Sweden)
  • 4 The Kennedy Centre, Dept. of Clinical Genetics, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. , (Denmark)
  • 5 Astrid Lindgren Children's Hospital, Karolinska University Hospital and Dept. of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden. , (Sweden)
  • 6 Institute of Clinical Research, University of Southern Denmark Odense, Odense, Denmark; Dept. of Clinical Genetics, Odense University Hospital, Denmark. , (Denmark)
  • 7 Dept. of Clinical Genetics, Skaane University Hospital, Lund, Sweden. , (Sweden)
  • 8 Dept. of Paediatrics, Skaane University Hospital, Lund, Sweden; Dept. of Clinical Sciences, Lund University, Sweden. , (Sweden)
  • 9 Dept. of Abdominal Surgery, Odense University Hospital, Denmark. , (Denmark)
  • 10 Dept. of Pediatric Surgery, Skaane University Hospital, Lund, Sweden. , (Sweden)
  • 11 Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark. , (Denmark)
  • 12 Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark; Institute of Clinical Research, University of Southern Denmark Odense, Odense, Denmark. , (Denmark)
  • 13 Dept. of Nuclear Medicine, Odense University Hospital, Odense, Denmark. , (Denmark)
  • 14 Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark; Institute of Clinical Research, University of Southern Denmark Odense, Odense, Denmark; Dept. of Pathology, Odense University Hospital, Odense, Denmark. , (Denmark)
Type
Published Article
Journal
European journal of medical genetics
Publication Date
Jan 01, 2020
Volume
63
Issue
1
Pages
103632–103632
Identifiers
DOI: 10.1016/j.ejmg.2019.02.004
PMID: 30797057
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Mosaic genome-wide paternal uniparental disomy (GW-pUPD) is a rarely recognised disorder. The phenotypic manifestations of multilocus imprinting defects (MLIDs) remain unclear. We report of an apparently non-syndromic infant with severe congenital hyperinsulinism (CHI) and diffuse pancreatic labelling by 18F*-DOPA-PET/CT leading to near-total pancreatectomy. The histology was atypical with pronounced proliferation of endocrine cells comprising >70% of the pancreatic tissue and a small pancreatoblastoma. Routine genetic analysis for CHI was normal in the blood and resected pancreatic tissue. At two years' age, Beckwith-Wiedemann Syndrome (BWS) stigmata emerged, and at five years a liver tumour with focal nodular hyperplasia and an adrenal tumour were resected. pUPD was detected in 11p15 and next in the entire chromosome 11 with microsatellite markers. Quantitative fluorescent PCR with amplification of chromosome-specific DNA sequences for chromosomes 13, 18, 21 and X indicated GW-pUPD. A next generation sequencing panel with 303 SNPs on 21 chromosomes showed pUPD in both blood and pancreatic tissue. The mosaic distribution of GW-pUPD ranged from 31 to 35% in blood and buccal swap to 74% in the resected pancreas, 80% in a non-tumour liver biopsy, and 100% in the liver focal nodular hyperplasia and adrenal tumour. MLID features included transient conjugated hyperbilirubinaemia and lack of macrosomia from BWS (pUPD6); and behavioural and psychomotor manifestations of Angelman Syndrome (pUPD15) on follow-up. In conclusion, atypical pancreatic histology in apparently non-syndromic severe CHI patients may be the first clue to BWS and multi-syndromal CHI from GW-pUPD. Variations in the degree of mosaicism between tissues explained the phenotype. Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

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