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

Christesen, Henrik Thybo ; Christensen, Lene Gaarsmand ; Löfgren, Åsa Mattsson ; Brøndum-Nielsen, Karen ; Svensson, Johan ; Brusgaard, Klaus ; Samuelsson, Sofie LU ; Elfving, Maria LU ; Jonson, Tord LU and Grønskov, Karen , et al. (2020) In European Journal of Medical Genetics 63(1).
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... (More)

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.

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type
Contribution to journal
publication status
published
subject
keywords
Angelman syndrome, Beckwith-Wiedemann syndrome, Congenital hyperinsulinism, Genome-wide uniparental disomy, Mosaicism
in
European Journal of Medical Genetics
volume
63
issue
1
article number
103632
publisher
Elsevier
external identifiers
  • pmid:30797057
  • scopus:85064242013
ISSN
1769-7212
DOI
10.1016/j.ejmg.2019.02.004
language
English
LU publication?
yes
id
2d53fb9b-48e6-43d0-ae52-d10ef2794ffd
date added to LUP
2019-05-09 12:13:31
date last changed
2021-06-23 01:24:25
@article{2d53fb9b-48e6-43d0-ae52-d10ef2794ffd,
  abstract     = {<p>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 &gt;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.</p>},
  author       = {Christesen, Henrik Thybo and Christensen, Lene Gaarsmand and Löfgren, Åsa Mattsson and Brøndum-Nielsen, Karen and Svensson, Johan and Brusgaard, Klaus and Samuelsson, Sofie and Elfving, Maria and Jonson, Tord and Grønskov, Karen and Rasmussen, Lars and Backman, Torbjörn and Hansen, Lars Kjaersgaard and Larsen, Annette Rønholt and Petersen, Henrik and Detlefsen, Sönke},
  issn         = {1769-7212},
  language     = {eng},
  number       = {1},
  publisher    = {Elsevier},
  series       = {European Journal of Medical Genetics},
  title        = {Tissue variations of mosaic genome-wide paternal uniparental disomy and phenotype of multi-syndromal congenital hyperinsulinism},
  url          = {http://dx.doi.org/10.1016/j.ejmg.2019.02.004},
  doi          = {10.1016/j.ejmg.2019.02.004},
  volume       = {63},
  year         = {2020},
}