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

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

*Corresponding author for this work

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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.

Original languageEnglish
JournalEuropean Journal of Medical Genetics
ISSN1769-7212
DOIs
Publication statusE-pub ahead of print - 1. Jan 2019

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Congenital Hyperinsulinism
Uniparental Disomy
Focal Nodular Hyperplasia
Glandular and Epithelial Neoplasms
Liver
Angelman Syndrome
Chromosomes, Human, Pair 18
Christianity
Chromosomes, Human, Pair 13
Chromosomes, Human, Pair 21
Chromosomes, Human, Pair 11
Pancreatectomy
Mosaicism
Endocrine Cells
Cheek
Single Nucleotide Polymorphism
Pancreas
Polymerase Chain Reaction
Neoplasms

Keywords

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

Cite this

@article{409b18d5aeca42218d69e2890d0871ce,
title = "Tissue variations of mosaic genome-wide paternal uniparental disomy and phenotype of multi-syndromal congenital hyperinsulinism",
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.",
keywords = "Angelman syndrome, Beckwith-Wiedemann syndrome, Congenital hyperinsulinism, Genome-wide uniparental disomy, Mosaicism",
author = "Christesen, {Henrik Thybo} and Christensen, {Lene Gaarsmand} and L{\"o}fgren, {{\AA}sa Mattsson} and Karen Br{\o}ndum-Nielsen and Johan Svensson and Klaus Brusgaard and Sofie Samuelsson and Maria Elfving and Tord Jonson and Karen Gr{\o}nskov and Lars Rasmussen and Torbj{\"o}rn Backman and Hansen, {Lars Kjaersgaard} and Larsen, {Annette R{\o}nholt} and Henrik Petersen and S{\"o}nke Detlefsen",
year = "2019",
month = "1",
day = "1",
doi = "10.1016/j.ejmg.2019.02.004",
language = "English",
journal = "European Journal of Medical Genetics",
issn = "1769-7212",
publisher = "Elsevier Masson",

}

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; Elfving, Maria; Jonson, Tord; Grønskov, Karen; Rasmussen, Lars; Backman, Torbjörn; Hansen, Lars Kjaersgaard; Larsen, Annette Rønholt; Petersen, Henrik; Detlefsen, Sönke.

In: European Journal of Medical Genetics, 01.01.2019.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Tissue variations of mosaic genome-wide paternal uniparental disomy and phenotype of multi-syndromal congenital hyperinsulinism

AU - Christesen, Henrik Thybo

AU - Christensen, Lene Gaarsmand

AU - Löfgren, Åsa Mattsson

AU - Brøndum-Nielsen, Karen

AU - Svensson, Johan

AU - Brusgaard, Klaus

AU - Samuelsson, Sofie

AU - Elfving, Maria

AU - Jonson, Tord

AU - Grønskov, Karen

AU - Rasmussen, Lars

AU - Backman, Torbjörn

AU - Hansen, Lars Kjaersgaard

AU - Larsen, Annette Rønholt

AU - Petersen, Henrik

AU - Detlefsen, Sönke

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - Angelman syndrome

KW - Beckwith-Wiedemann syndrome

KW - Congenital hyperinsulinism

KW - Genome-wide uniparental disomy

KW - Mosaicism

UR - http://www.scopus.com/inward/record.url?scp=85064242013&partnerID=8YFLogxK

U2 - 10.1016/j.ejmg.2019.02.004

DO - 10.1016/j.ejmg.2019.02.004

M3 - Journal article

JO - European Journal of Medical Genetics

JF - European Journal of Medical Genetics

SN - 1769-7212

ER -