Send to

Choose Destination
J Pediatr Endocrinol Metab. 2019 Sep 4. pii: /j/jpem.ahead-of-print/jpem-2019-0261/jpem-2019-0261.xml. doi: 10.1515/jpem-2019-0261. [Epub ahead of print]

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

Author information

Department of Paediatrics, 2Faculty of Medicine, Charles University in Prague, University Hospital Motol, Prague, Czech Republic.
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
Department of Paediatric Haematology and Oncology, 2Faculty of Medicine, Charles University in Prague, University Hospital Motol, Prague, Czech Republic.


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.


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


Supplemental Content

Full text links

Icon for Sheridan PubFactory
Loading ...
Support Center