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

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 labelli...

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Bibliographic Details
Published in:	European journal of medical genetics Vol. 63; no. 1; p. 103632
Main Authors:	Christesen, Henrik Thybo, Christensen, Lene Gaarsmand, Löfgren, Åsa Mattsson, Brøndum-Nielsen, Karen, Svensson, Johan, Brusgaard, Klaus, Samuelsson, Sofie, Elfving, Maria, Jonson, Tord, Grønskov, Karen, Rasmussen, Lars, Backman, Torbjörn, Hansen, Lars Kjaersgaard, Larsen, Annette Rønholt, Petersen, Henrik, Detlefsen, Sönke
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier Masson SAS 01-01-2020
Subjects:	Angelman syndrome Basic Medicine Beckwith-Wiedemann syndrome Congenital hyperinsulinism Genome-wide uniparental disomy Medical and Health Sciences Medical Genetics Medicin och hälsovetenskap Medicinsk genetik Medicinska och farmaceutiska grundvetenskaper Mosaicism Beckwith-Wiedemann syndrome Mosaicism Angelman syndrome Congenital hyperinsulinism Genome-wide uniparental disomy
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Summary:	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.
Bibliography:	ObjectType-Case Study-2 SourceType-Scholarly Journals-1 ObjectType-Feature-4 content type line 23 ObjectType-Report-1 ObjectType-Article-3
ISSN:	1769-7212 1878-0849 1878-0849
DOI:	10.1016/j.ejmg.2019.02.004