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Journal of Pediatric Endocrinology and Metabolism

Editor-in-Chief: Kiess, Wieland

Ed. by Bereket, Abdullah / Darendeliler, Feyza / Dattani, Mehul / Gustafsson, Jan / Luo, Fei Hong / Mericq, Veronica / Toppari, Jorma


IMPACT FACTOR 2018: 1.239

CiteScore 2018: 1.22

SCImago Journal Rank (SJR) 2018: 0.507
Source Normalized Impact per Paper (SNIP) 2018: 0.562

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2191-0251
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Volume 32, Issue 10

Issues

Screening of monogenic autoimmune diabetes among children with type 1 diabetes and multiple autoimmune diseases: is it worth doing?

Veronika Strakova
  • Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague, University Hospital Motol, Prague, Czech Republic
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/ Lenka Elblova
  • Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague, University Hospital Motol, Prague, Czech Republic
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/ Matthew B. Johnson / Petra Dusatkova
  • Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague, University Hospital Motol, Prague, Czech Republic
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/ Barbora Obermannova
  • Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague, University Hospital Motol, Prague, Czech Republic
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/ Lenka Petruzelkova
  • Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague, University Hospital Motol, Prague, Czech Republic
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/ Stanislava Kolouskova
  • Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague, University Hospital Motol, Prague, Czech Republic
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/ Marta Snajderova
  • Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague, University Hospital Motol, Prague, Czech Republic
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/ Eva Fronkova
  • Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University in Prague, University Hospital Motol, Prague, Czech Republic
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/ Michael Svaton
  • Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University in Prague, University Hospital Motol, Prague, Czech Republic
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/ Jan Lebl
  • Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague, University Hospital Motol, Prague, Czech Republic
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/ Andrew T. Hattersley / Zdenek Sumnik
  • Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague, University Hospital Motol, Prague, Czech Republic
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/ Stepanka PruhovaORCID iD: https://orcid.org/0000-0003-2076-115X
Published Online: 2019-09-04 | DOI: https://doi.org/10.1515/jpem-2019-0261

Abstract

Background

Paediatric type 1 diabetes (T1D) and rare syndromes of monogenic multi-organ autoimmunity share basic features such as full insulin dependency and the presence of circulating beta-cell autoantibodies. However, the aetiopathogenesis, natural course and treatment of these conditions differ; therefore, monogenic multi-organ autoimmunity requires early recognition. We aimed to search for these monogenic conditions among a large cohort of children with T1D.

Methods

Of 519 children with T1D followed-up in a single centre, 18 had multiple additional autoimmune conditions – either autoimmune thyroid disease (AITD) and coeliac disease (CD) or at least one additional organ-specific autoimmune condition in addition to AITD or CD. These 18 children were tested by direct Sanger sequencing (four patients with a suggestive phenotype of immune dysregulation, polyendocrinopathy, enteropathy, X-linked [IPEX] or signal transducer and activator of transcription 3 [STAT3]- and cytotoxic T-lymphocyte protein 4 [CTLA4]-associated syndromes) or by whole-exome sequencing (WES) focused on autoimmune regulator (AIRE), forkhead box protein 3 (FOXP3), CTLA4, STAT3, signal transducer and activator of transcription 1 (STAT1), lipopolysaccharide-responsive and beige-like anchor protein (LRBA) and interleukin-2 receptor subunit α (IL2RA) genes. In addition, we assessed their T1D genetic risk score (T1D-GRS).

Results

We identified novel variants in FOXP3, STAT3 and CTLA4 in four cases. All patients had a severe phenotype suggestive of a single gene defect. No variants were identified in the remaining 14 patients. T1D-GRS varied among the entire cohort; four patients had scores below the 25th centile including two genetically confirmed cases.

Conclusions

A monogenic cause of autoimmune diabetes was confirmed only in four patients. Genetic screening for monogenic autoimmunity in children with a milder phenotype and a combination of AITD and CD is unlikely to identify a monogenic cause. In addition, the T1D-GRS varied among individual T1D patients.

Keywords: CTLA4; IPEX syndrome; monogenic autoimmune diabetes; STAT3; T1D-GRS

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About the article

Corresponding author: Stepanka Pruhova, MD, PhD, Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague, University Hospital Motol, V Uvalu 84, 150 06 Prague 5, Czech Republic, Phone: +420 224 432 026, Fax: +420 224 432 221


Received: 2019-06-09

Accepted: 2019-08-09

Published Online: 2019-09-04

Published in Print: 2019-10-25


Funding Source: Ministry of Health of the Czech Republic

Award identifier / Grant number: NV18-01-007

The study was funded by the Grant Agency of Charles University in Prague (no. GAUK 216217), the Ministry of Health of the Czech Republic (funder Id: http://dx.doi.org/10.13039/501100003243) (no. NV18-01-0078) and the Welcome Trust Senior Investigator Award (no. 098395/Z/12/Z).


Author contributions: VS analysed the data and wrote the manuscript; SP designed the study and reviewed/edited the manuscript; LE analysed the data and wrote the manuscript; MBJ researched data and reviewed/edited the manuscript; ATH reviewed/edited the manuscript; PD designed the study and reviewed/edited the manuscript; BO investigated the patients; LP investigated the patients and reviewed/edited the manuscript; SK investigated the patients and reviewed/edited the manuscript; MaS investigated the patients; JL reviewed/edited the manuscript; ZS reviewed/edited the manuscript; EF analysed the data and reviewed/edited the manuscript; MiS analysed the data and reviewed/edited the manuscript. All authors made substantial contributions to the acquisition and interpretation of data, revised the manuscript critically for important intellectual content and approved the final version to be published. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organisation(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.


Citation Information: Journal of Pediatric Endocrinology and Metabolism, Volume 32, Issue 10, Pages 1147–1153, ISSN (Online) 2191-0251, ISSN (Print) 0334-018X, DOI: https://doi.org/10.1515/jpem-2019-0261.

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