Case report: type 1 diabetes in monozygotic quadruplets

• Published in: European journal of human genetics : EJHG Vol. 20; no. 4; pp. 457 - 462
• Main Authors: STECHOVA, Katerina, HALBHUBER, Zbynek, SPISEK, Radek, SEDIVA, Anna, FILIPP, Dominik, SUMNIK, Zdenek, HUBACKOVA, Miluse, KAYSEROVA, Jana, PETRUZELKOVA, Lenka, VCELAKOVA, Jana, KOLOUSKOVA, Stanislava, ULMANNOVA, Tereza, FARESJÖ, Maria, NEUWIRTH, Ales
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.04.2012
• Subjects: Antibodies; Autoimmune diseases; Autoimmunity; Beta cells; Biological and medical sciences; Child, Preschool; cytokine array; Cytokines; Dendritic cells; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Diabetes. Impaired glucose tolerance; DNA methylation; DNA microarrays; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; enteroviral infection; Enterovirus; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Families & family life; Female; Fundamental and applied biological sciences. Psychology; Gene expression; gene expression array; General aspects. Genetic counseling; genetic predisposition to diabetes; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Health sciences; Hospitals; Humans; Immunoglobulins; Immunoregulation; Infections; Insulin; Interleukin 27; Interleukin 9; Islets of Langerhans; Laboratories; Lymphocytes; Lymphocytes T; Medical genetics; Medical sciences; MEDICIN; MEDICINE; Molecular and cellular biology; monozygotic quadruplets; Pancreas; Pathogenesis; Quadruplets; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; type 1 diabetes; Viral infections; α-Interferon; United States > US; Czech Republic; Sweden; Endocrinopathy; Immunopathology; enteroviral infection; cytokine array; genetic predisposition to diabetes; Cytokine; Autoimmune disease; Gene expression; Genetic determinism; Case study; Infection; monozygotic quadruplets; Type 1 diabetes; Genetics; gene expression array
• ISSN: 1018-4813; 1476-5438; 1476-5438
• DOI: 10.1038/ejhg.2011.212

Type 1 diabetes (T1D) is an autoimmune disease characterized by the lack of insulin due to an autoimmune destruction of pancreatic beta cells. Here, we report a unique case of a family with naturally conceived quadruplets in which T1D was diagnosed in two quadruplets simultaneously. At the same time, the third quadruplet was diagnosed with the pre-diabetic stage. Remarkably, all four quadruplets were positive for anti-islet cell antibodies, GAD65 and IA-A2. Monozygotic status of the quadruplets was confirmed by testing 14 different short tandem repeat polymorphisms. Serological examination confirmed that all quadruplets and their father suffered from a recent enteroviral infection of EV68-71 serotype. To assess the nature of the molecular pathological processes contributing to the development of diabetes, immunocompetent cells isolated from all family members were characterized by gene expression arrays, immune-cell enumerations and cytokine-production assays. The microarray data provided evidence that viral infection, and IL-27 and IL-9 cytokine signalling contributed to the onset of T1D in two of the quadruplets. The propensity of stimulated immunocompetent cells from non-diabetic members of the family to secrete high level of IFN-α further corroborates this conclusion. The number of T regulatory cells as well as plasmacytoid and/or myeloid dendritic cells was found diminished in all family members. Thus, this unique family is a prime example for the support of the so-called 'fertile-field' hypothesis proposing that genetic predisposition to anti-islet autoimmunity is 'fertilized' and precipitated by a viral infection leading to a fully blown T1D.