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

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  • Henrik Thybo Christesen
  • Lene Gaarsmand Christensen
  • Åsa Mattsson Löfgren
  • Karen Brøndum-Nielsen
  • Johan Svensson
  • Klaus Brusgaard
  • Sofie Samuelsson
  • Maria Elfving
  • Tord Jonson
  • Karen Grønskov
  • Lars Rasmussen
  • Torbjörn Backman
  • Lars Kjaersgaard Hansen
  • Annette Rønholt Larsen
  • Henrik Petersen
  • Sönke Detlefsen
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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.

Original languageEnglish
JournalEuropean Journal of Medical Genetics
Volume63
Issue number1
Pages (from-to)103632
ISSN1769-7212
DOIs
Publication statusPublished - Jan 2020

    Research areas

  • Angelman syndrome, Beckwith-Wiedemann syndrome, Congenital hyperinsulinism, Genome-wide uniparental disomy, Mosaicism

ID: 58250528